I

suppose youre using this because its more convenient than flipping through over 100 pages of notes. Ive condensed the Parasitology, Mycology, and Virology down to about 24 pages. Just a few words of caution: Although Ive based it on the notes, there may be errors so definitely check out the actual notes. Ive used some abbreviations: RT = Respiratory Tract, URT = Upper RT, LRT = Lower RT, Ab = Antibody, RNA Pol II = RNA Polymerase II, RES = Reticulocyte-Endothelial System. If theres something that Ive included that makes no sense at all, let me know and Ill correct it. Towards the end, the Retrovirus life cycle is complicated. Ive simplified it a bit; what Ive included is what you mainly need to know but just see the figures in the actual notes. I havent added in all the retroviruses either but there are only a few so youll easily be able to review that from the actual notes. It has been designed such that you can read through the whole thing or just read the bolded words (quick review) and still capture the pertinent information. Email me if you have any comments, corrections, or whatever. Enjoy! Best, Nitesh V Patel patel236@umdnj.edu

Pathogenic Flagellates
1) Giardia lamblia
Common cause of Backpackers Diarrhea; poor sanitation. Acquired through contaminated natural waters. Multiplies in mammalian intestine, cells and cysts shed in feces, then contaminate water. Cells have two-nuclei and a large ventral sucker-disc used for intestinal adherence; looks like a face. Organisms adhere to brush border, thus limit absorption. Chronic and acute diarrhea. Treat with Metronidazole, prevent via boiling of water, use of iodine pills, or filtration. Sexually transmitted multiplies on GU Mucosal membranes. Cells have a polar tuft of flagella and an undulating membrane. Women: infection of genitalia, vagina, and cervix with itching and pale-yellow watery discharge. Men: urethral infection can be local or extend to prostate / seminal vesicles, discharge may be absent. Treat with Metronidazole; also treat sexual partners. Have a characteristic Kinetoplast which is a mitochondrion-basal body like organelle. Have distinct stages within the life cycle: Amastigote (Nucleus & Kinetoplast central), Promastigote (Kinetoplast anterior, flagellum), Epimastigote (Kinetoplast central, flagellum, half undulating membrane), and Trypomastigote (Kinetoplast posterior, flagellum, full undulating membrane). Transmitted via Tsetse Fly and multiply in both vector and host. Induces blood stream infections and multiply outside of cells; cells are elongate with single flagellum.

2) Trichomonas vaginalis (STD)

3) Hemoflagellates

A) Trypanosoma bruceii

Three major species: Trypanosoma bruceii bruceii (East Africa), Trypanosoma bruceii rhodesiense (East Africa), Trypanosoma bruceii gambesiense (West Africa). Only latter two are infectious in humans. All multiply as Epimastigotes in Tsetse Fly gut, and as Trypomastigotes in human bloodstream. Disease has three stages: Localized Inflammatory Lesion (local; then blood bound), Acute Blood Stream Phase (fever, joint pains; enlarged Posterior Cervical Lymph Nodes = Winterbottoms sign), Chronic Stage (invasion of CNS). Surface Glycoproteins can vary due to variation via silent and expressed gene copies; thus infection occurs in waves. Patients may have highly elevated IgM levels (20x) due to repeated bouts. Treat wit Anti-Trypanosomal Drugs Early Stage = Suramin and Pentamidine, CNS Stage = Melarsoprol and Difluoromethylornithine.

A.1) T. b. rhodesiense A.2) T. b. gambesiense

Produces slowly progressive infections and has a reservoir in humans. Produces rapidly progressive infections and has a reservoir ungulates.

B) Trypanosoma cruzeii
Causes what is also known as Chagas Disease. Comes from the Triatoma bug. Multiply as Promastigotes in the bug gut and are excreted in bug feces. Bug feces left on skin, then human scratch pushes infected feces into bug bite. Multiply intracellularly in humans as Amastigotes. Migrate via blood stream as Trypomastigotes. Initial Stage: disease begins with primary lesion and regional lymphadenitis. Autoinoculation of conjunctiva unilateral eyelid swelling (Romanasign). Middle Stage: Amastigotes multiply in muscle tissue along with hepatosplenomegaly. Late Stage: Invasion of the heart, PNS problems, excessive intestinal and esophageal enlargement. Diagnosed via seroconversion or muscle biopsy. Treat with Azoles for American Trypanosomiasis; kill blood forms with Gentian Violet.

C) Leishmania
Causes visceral and mucocutaneous infections; transmitted via Sandfly in tropics and subtropics. Multiply in the gut of Sandfly as Promastigotes and inside Macrophages and RES as Amastigotes. Release into bloodstream via lysis. Leishmania donovani and Leishmania chagasii produce visceral Leishmaiansis or Kala-Azar as a result of hepatospleno-multiplication. Amastigotes in tissue = called Leishman-Donovan Bodies. Dermotrophic leishmaniasis leads to dermotropic ulcerative lesions which can be visceral or all over. Leishmania braziliensis spreads via muco-ciliary-membranes leading to Espundia. Treat with Hexadecylphosphocholine.

Amoeba & Amoeboflagellates

D) Entamoeba histolytica
Causes Amoebic Dysentery Ingested in Cyst form, turns to Trophoziote form, which then multiplies into more Cysts and Trophozoites, which spread via feces. Trophozoites are Larger than other species, have vacuoles with RBCs while non-pathogenic have vacuoles with Bacteria. Cyst form is round and tetra-nucleated. Also characteristic chromatid bodies with round ends. Infest intestinal crypts and spread laterally in muscularis mucosa leading to a flask-shaped lesion. Blood, mucous, and amoebas flow into lumen. Ulcers contain Trophozoites, while Cysts form only in Lumen. Symptoms include: Mild Case diarrhea, cramps, nausea, and malaise; Severe Case Dysentery.

Treat with Metronidazole.

E) Naegleria fowleri & Others

Brain-eating amoebas: N. fowleri, Hartmanella, and Acanthamoeba. Infection from invasion during swimming in natural waters. Enter from nose and pass to Brain via Cribiform Plate. Rapidly progressive, kills within a week. Acanthamoeba may cause keratitis (contaminated contact-lens solution). Treat with Amphotericin + Azoles. Are Photosynthetic protozoa. Contracted via consumption of shellfish. Pfeisteria piscidida toxins can cause serious human neurological poisoning.

F) Dinoflagellates

Ciliates
1) Balantidium coli
Produces dysentery like E. histolytica. Diagnosis is made by organism present in stool Trophozoite form is large, with kidney-shaped macronucleus and polar feeding apparatus. Cysts are large and round. Similar in appearance to Paramecium much larger than RBC. Treat with Tetracyclines or Metronidazole.

Apicomplexa
Have a sexual and an asexual reproduction cycle dependent on if host is definitive or intermediate. In the asexual phase, multiple nuclear divisions lead to the production of multiple uninucleated cells. In the sexual phase two types of gametes (micro- vs. macro-) combine to form the zygote.

1) Plasmodium
Four major types: P. falciparum, P. malariae, P. ovale, P. vivax Plasmodium has a complicated life cycle involving sporozoite replication in the human liver, merozoite release, merozoite entry into blood and RBCs, gametocyte formation, RBC lysis, uptake of gametocytes by vector (mosquito), meiosis of gametes in vector, followed by cyst formation (via fusion of gametes) in vector gut wall, then sporozoite formation, transfer to mosquito saliva, entry into human via mosquito bite, entry into liver and reiteration. Life cycle has two phases: Erythrogenic Phase and Exoerythrogenic Phase. Liver phase is the Exoerythrogenic phase. Erythrogenic Phase is diagnostic involves successive phases: Ring Form, Trophozoite, Schizont (via Schizogeny), followed by RBC lysis. Plasmodia degrade hemoglobin, leading to hemin granules (= Malarial Pigment), which are phagocytosed by cells of the RES. P. vivax and P. ovale are the least severe with fevers at 48 hr intervals (benign tertian, days 1,3,6). But the Plasmodium persists in the liver for years as a hypnozoite. P. malariae is a more severe form that delivers fever at 72 hr intervals (Quartan, days 1,4,8). No liver persistence but has a mild long-term persistence in blood.

Phase

P. falciparum is the most severe form that delivers fever at 48 hr intervals (Malign tertian, 1,3,6). No liver persistence. Diagnosis is made based on blood smear using the guidelines in the table below. P. vivax P. ovale P. malariae P. falciparum

RBC Attack Level Ring Forms

Low (Reticulocytes) Large, 1 Ring/RBC

Low(Reticulocytes) Large, 1 Ring/RBC

Low (Senescent) Large, 1 Ring/RBC

High (All stages) Small, >1 Ring/RBC, Appliqu Forms, adjacent to Plasma membrane Rare / Absent, RBC clump together due to adhesion factors Rare / Absent, RBC clump together due to adhesion factors Banana-Shaped, or sickle-shaped.

Trophozoite

Pleomorphic

Oval, flared RBC Surface

Band / Rectangular Shaped

Schizont

>12 Progeny / RBC

<12 Progeny / RBC, Rosette clusters Round / Oval

<12 Progeny / RBC, Rosette clusters Round / Oval

Gametes

Round / Oval

Symptoms of malarial disease include: headache, nausea, and malaise. As the disease progresses anemia, cachexia, along with hepatosplenomegaly develop. Blackwater fever also develops from severe hemolysis (P. falciparum). In cases P. falciparum, RBCs may adhere to each other leading to possible occlusion. This occlusion may spread to other organ systems; cerebral malaria may result (strokes likely). Resulting immunosuppresion may increase incidence of Epstein Barr, B-Cell Lymphomas (Burkittss Lymphoma). Immunity may result for antigenically similar strains. Treatment options include Chloroquine (blood forms and gametocytes), Primaquine (liver forms), Quinine / Quinidine + Doxycycline (Cerebral Malaria), Fansidar (combination of Quinine and sulfa; for Chloroquine resistance), Artemisinin (Blood forms incl. gametocytes; combination therapy). Prophylaxis involves exposure protection measures along with drugs such as Chloroquine, Mefloquine (Chloroquine resistance), Doxycycline (not for pregnant women), and malarone.

2) Babesia microti
Reservoir: dogs, livestock Vector: tick Malaria-like illness with Ring-forms on Blood Smear, some cross shaped. Treat with Clindamycin + Quinine Spread via the Fecal / Oral route, and contaminated water.

3) Cryptosporidium parvum

Produces diarrhea; diagnosis via fecal smear for acid-fast cysts produced No effective treatment options; only supportive care Spread via the Fecal / Oral Route Diagnosis via fecal smear; produces diarrhea, fever, abdominal pain Treat with TM/Sulfa if severe

4) Isospora belli

5) Cyclospora cayetnensis
Spread via the Fecal / Oral route, and contaminated vegetables / fruit. Diagnosis via fecal smear for acid-fast cysts; produces diarrhea. Treat with TM/Sulfa

6) Toxoplasma gondii
Found in cat feces as oocysts which multiply as tachyzoites in the human gut. Then transport via macrophages to other body areas. Cysts are common in meat that is uncooked or raw and also common in Cat Litter. Pregnant women should avoid changing cat litter since severe congenital infection may result after primary infection of mother. May lead to infantile retinal disease common cause of blindness. Treat with TM/Sulfa

Fungi
1) Superficial Mycoses
Produced by fungi of low virulence; little inflammation Skin infections: Pityriasis (group of flaky skin conditions), with hyper- / hypo- inflammation Piedra, or growth in or on hair shafts, may occur. Diagnosis via microscopy and a Woods UV Lamp.

2) Cutaneous Mycoses
Fungi that cause them are Dermatophytes. Infections are called Tinea, followed by the name if the infected area; include: tinea corporis (ringworm on skin), tinea capitis (scalp), tinea cruris (jock itch, groin), tinea pedis (athletes foot), tinea unguium (nails), and tinea barbae (beard). Lesions expand in a ring pattern with inflammation, while center heals. Diagnosis made based on the presence or absence of microconidia, and appearance of macroconidia. Three important genera: Epidermophyton, Microsporum, and Trichophyton. Infect subcutaneous tissue; localized usually. Exposure is usually occupational. Lesions often on extremities, with ulcers and papules. Subcutaneous mass with granulamatous inflammation may form (Mycetoma).

3) Subcutaneous Mycoses

Similar lesions are formed by Actinomycetes, but obviously causative organism is different. Common organisms include: Sporothrix schenkii (Dimorphic yeast fungi), leading to sporotrichosis. Diagnosed via microscopy revealing long, cigar-shaped, budding cells.

4) Systemic Mycoses
Endemic to a particular geographic area; immune-suppressed individuals most vulnerable. Primary infections are usually in the lung, and can become systemic. Organisms are dimorphic as yeast in tissue. Exposure is often occupational thus males are more prone. There are a few types:

A) Blastomyces dermatitidis
Large broad-based yeast buds larger than others in tissue. Endemic east of the Mississippi , in beaver dams and river banks Tiny budding yeast; smaller than others; often inside macrophages. Form tuberculate macroconidia in culture; yeast in tissue but intracellular. Endemic in the Ohio River area; in bird/bat feces-enriched soils. Large spherules, containing multiple endospores in tissue. Arthoconidia in culture Endemic in the Southwest U.S. found in desert soil. Large yeast with multiple buds in tissue. Primarily found in Central and South America in the Soil Multiple buds with a ships wheel appearance Common to the GI Tract and Mucosa normal flora. Multiple forms in tissue: Hyphae, pseudohyphae, yeast (extracellular). In culture, forms include Hyphae, pseudohyphae, yeast, and chlamydospores. Endemic virtually everywhere. Form characteristic Germ Tubes in serum. Vaginal infections common in women and incidence increases with immunosuppresion (pregnancy, diabetes, hormone/antibiotic therapy). GI Infections in infants, spread to oral and peri-anal regions. Also with Catheters. GI infections can spread to the oral areas and lead to Thrush. Chronic Mucocutaneous Candidiasis is hallmark with Cell Mediated Immunity deficits. Heavily encapsulated yeast in tissue and culture; dimorphic. Found virtually everywhere; in soil and bird droppings. Can lead to CNS infections, lung infections due to spread from lungs since encapsulated.

B) Histoplasma capsulatum

C) Coccidioides immitis

D) Paracoccidioides braziliensis

E) Candida albicans

F) Cryptococcus neoformans

5) Opportunistic Fungal Pathogens

Ubiquitous and important pathogens of AIDS patients, transplant recipients, and anticancer therapy patients.

A) Aspergillus

A large genus that is ubiquitous in soil and plant material. Most frequent pathogen is Aspergillus fumigatus Infections are usually pulmonary and local or invasive/necrotizing. If they cross the vessel epithelia, they may cause thrombosis, infarcts, necrosis, and hemorrhage, along with systemic spread. Common in the occupationally exposed and those with topic allergies. Treat with Amphotericin/Fluorocytosine or Azoles.

B) Zygomyces
Common species are Mucor and Rhizopus. Causes URT and LRT infections in immunosuppressed patients; can spread to CNS (Rhinocerebral zygmycosis). Grow with right-angle branching Hyphae with limited or no septae. Ubiquitous organism virtually 100% of the U.S. has Antibodies must be caught in childhood. Cannot be cultured except in the immunosuppressed and samples have stained small oval forms or larger cyst forms. Diagnosis made on Broncho-alveolar Lavage Fluid Stain. Treat with prophylaxis via Pentamidine and TM/Sulfa.

C) Pneumocystis jirovecii (carinii)

6) Microsporidia
Resemble Protozoa but are more related to animals and fungi. Three genera that infect humans: Encephalitozoon, Enterocytozoon, Nosemia. Follows a lifestyle similar to that of Plasmodium attack cell, turn to a Trophozoite, multiply intracellularly, form into a Schizont, then causes cell lysis. Have the smallest eukaryote genome. Cause mostly intestinal, eye, or systemic infections. Can be spread transplacentally. Diagnosis based on special stains of samples from urine, stools, or exudate. Treat with Albendazole for intestinal infections and other Azoles for eye infections.

Positive Strand RNA Viruses

All viruses that are under the Positive-Strand RNA category have: (A) Positive-Strand RNA, (B) Non-segmented genome. Also, virions contain no enzymes and viral proteins are made as polyproteins. They replicate in the cytoplasm.

1) Picornaviridae
Poliovirus is the most widely known and researched. Three major Genera exist: Enteroviruses, Rhinoviruses, and Hepatoviruses. Enteroviruses include: Poliovirus, Coxsackieviruses, ECHO Viruses, and Enteroviruses 68-71. Rhinoviruses are composed of over 100 serotypes and are Acid-Labile (unlike Enteroviruses). Hepatoviruses include: Hepatitis A Virus (HAV).

A) Enteroviruses (all are spread via the fecal-oral route).

I)

Poliovirus
A disease of antiquity used to be called infantile paralysis. Polio = grey for grey matter and myelitis = inflammation of the spinal cord. Small virus with Positive-Sense-ssRNA. Non-enveloped and Icosahedral with 4 structural proteins: VP1, VP2, VP3, and VP4.

1 copy of each protein grouped into a Protomer, 5 Protomers grouped into a Pentamer/Capsomer, and 12 Pentamers grouped into the whole virus; thus a total of 60 copies of each structural protein. Three serological types, called: Type 1, Type 2, and Type 3. Replication occurs completely in the Cytoplasm. Begins with attachment to a CD155 Immunoglobulin family receptor, enters via RME, viral RNA is Positive Sense thus is translated, products arranged to replicate genome even more and create the needed structural proteins for new virion assembly. Genome is a single Long Open Reading Frame (ORF) thus viral protein synthesized as one long polyprotein, then cleaved into about 11 different proteins. First cleavage of polyprotein yields P1, P2, and P3. P1 gives rise to VP1, VP2, VP3, and VP4 while P2 and P3 give rise to non-structural proteins. P2 gives rise to 2A, 2B, and 2C and P3 gives rise to 3A, 3B, 3C, and 3D. 2A and 3C are the proteases that form P1, P2, and P3 from the polyprotein while 3D is the RNA- Dependent RNA Polymerase, and 3B is called VPg. RNA has a genetically encoded polyA 3-Tail but no 5-Cap. Instead VPg caps the 5-end. 5-end also contains the Internal Ribosome Entry Site (IRES) since there is no 5-methyl-cap. IRES allows for 40S Ribosome attachment and translation. Highly cytopathic; the 2A protease cleaves the Cap-Binding Complex required for host-mRNA translation and thus Host Cell protein synthesis is shut down. Virus infects man via GI tract (its Acid-Resistant), infects epithelia, produces viremia, then seeds into Anterior Horn Cells of the Spinal Cord. This leads to Lower Motor Neuron cell death and thus Flaccid Paralysis. Spread via fecal-oral route the four Fs + water. Clinical picture: acute onset LMN Syndrome with Flaccid Paralysis. Diagnosis via: Throat Swab, Stool, CSF, and an Ab Titer rise. Vaccination via Salk Vaccine (Formalin inactivated or killed) or Sabin vaccine (Live attenuated). Immunization against all three types is necessary. Live attenuated virus may mutate back to infectious form, leading to disease.

II)

Coxsackievirus
Two major groups, each with serotypes: Group A 23 Serotypes and Group B 6 Serotypes. Produces variable clinical syndromes and rarely, Polio-like syndrome.

III)

ECHO Viruses
Name since they were once thought to be Enteric Cytopathic Human Orphan Viruses. Initially produced asymptomatic disease but now are associated with varied clinical syndromes. Found in the stool of infected patients.

IV)

Enteroviruses 68-71
Numbered rather than named. Enterovirus 71 produces Hand, Foot, and Mouth Disease among young children and infants. Produces ulceration of the mouth and rash of the hands and feet. May also cause severe CNS Disease. Enterovirus 70 produces Acute Hemorrhagic Conjunctivitis. May lead to cardiopulmonary failure in serious cases. Over 100 Serotypes, mostly cause the Common Cold. Acid Labile and thus are destroyed by gastric acid.

B) Rhinoviruses

Require 33-35 Degrees (C) for growth thus grow best in the URT and Nasal Cavity. Hand-to-hand transmission very common as with respiratory droplets. Causes Infectious Hepatitis with an incubation of 2-6 weeks. Transmitted via the Fecal-Oral route; contaminated water / veggies. Produces hepatomegaly but recovery and prognosis is very good. Some may suffer liver damage.

C) Hepatovirus Hepatitis A Virus

2) Flavidiridae
Non-segmented Positive strand. Enveloped with 2 envelope proteins and 1 capsid protein. Transmitted via mosquitoes and some via ticks thus are Arboviruses. Three major genera: Flavivirus, Pestivirus, and Hepacvirus. Pestivirus do not cause human infections. All are enveloped, spherical and have spikes twice the size of poliovirus. Have 3 different proteins - C Protein and 2 membrane proteins: E-Protein (makes spikes) involved in attachment and fusion, M protein is the membrane protein. RNA is non-segmented and Positive-Sense-Strand with a 5-cap but no 3-PolyA Tail. Single ORF Polyprotein is product, and then cleaved; as with Poliovirus, 5-Cap side encodes structural proteins. Budding of virus occurs at cytosolic membranes (Golgi) not plasma membrane. No specific treatment only prevention through vector (mosquito or tick) control.

A) Flaviviruses

I)

St. Louis Encephalitis Virus (SLEV)

Mosquito is the vector; cycle between birds and mosquitoes human accidental host. Humans are only infected via mosquito, not another human. Virus alternates between vector and host. Causes moderately severe encephalitis associated with some mortality; asymptomatic stage and subclinical infection follow encephalitis. Affects mostly older patients >55 years old but most infections are asymptomatic. Similar in clinical presentation to West Nile Virus. Presents as fever, rash, joint pains, and severe debilitation often called break-bone fever. Normally cycles between mosquitoes and higher primates (including humans). Major mosquito vector is Aedes aegypti breeds in stagnant water including pails and tires. There are 4 different serotypes of virus. Neutralizing against one doesnt protect against the others. Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) both due to immunological enhancement in which recovery and response to one serotype can lead to enhanced immune response if infection by another serotype occurs. Due to the shared but not identical antigens between serotypes antibodies to one can partially attach to another serotype (although only to opsonize not neutralize) and still lead to a macrophage / cytokine response. Since macrophages are the target cell, this propagates the infection. Dengue is endemic in the Caribbean, especially Cuba, Dominican Republic, and Puerto Rico and has surfaced in Brazil.

II)

Dengue Fever Virus

III)

Yellow Fever Virus

Transmitted via mosquito vector; Human-to-mosquito-to-human normally. Produces systemic infection and can involve liver destruction, hemorrhagic / renal complications, and even death. Cycles between mosquitoes and higher primates (including humans) 2 forms, Jungle YF and Urban YF. Major mosquito vector is Aedes aegypti. Birds are vertebrate host, but pigs also infected to serve as an amplifying reservoir. Mosquitoes can cycle between pigs /birds and humans. Mosquito transmitted and cycles between Birds and Mosquitoes Human is accidental host (just like SLEV). Human only infected by arthropod; no human-human transmission since virus must alternate hosts. Cases few in the U.S. but reported in western states and Canada. Part of the Genus Flavivirus but are transmitted by ticks.

IV)

Japanese Encephalitis Virus (JEV)

V)

West Nile Virus

VI)

Tick-Bourne Encephalitis and Russian Spring-Summer Encephalitis Viruses

B) Hepacvirus (HCV)
Similar in infection to Hepatitis B Virus but known as Hepatitis C Virus. Spread via blood / body fluids. Single-stranded RNA that is non-segmented with Positive-Sense Polarity. Genome ha a single long ORF which yields a large polyprotein that is cleaved to 10 products. There are 3 structural proteins: C or Capsid Protein which combines with Viral RNA to form Nucleocapsid. Proteins E1 and E2 are membrane / envelope proteins with binding sites for CD81. Other proteins are non-structural: NS5B, is the RNA-Dependent RNA Polymerase, NS3 is the protease and RNA Helicase. Replicates similar to Flavivirus, but is similar to Picornaviridae with no 5-cap and instead an IRES. Infected individuals develop persistent viremia (chronic infection), Hepatic Cirrhosis, and Hepatocellular Carcinoma. Co-infection with HIV worsens course. Diagnosis via serology for anti-HCV Antibodies via Enzyme Immunoassays and Immunoblots (Westerns). Detection of HCV RNA in blood via a quantitative load measurement can be used to determine recovery levels. Assessment of liver disease is accomplished via serum Alanine-Aminotransferase levels. Treat with Interferon-Alpha and Ribavirin, monitor via ALA-Aminotransferase level measurements. Acute disease with jaundice is uncommon for cases of HCV. However Chronic Infection is very common in HCV Cases. As an aside, for cases of HBV, treat with Interferon-Alpha and Lamivudine. There is no vaccination available for HCV but there are vaccinations for both HBV and HAV.

3) Togaviridae
A) Alphaviruses
About 28 types; Spherical-Icosahedral particles enveloped and spiked. Virion contains 3 proteins: 2 envelope Glycoproteins which make up the spikes while the 3rd protein is the C protein which complexes with the RNA forming the nucleocapsid. Non-segmented Positive Sense RNA with 5-cap and PolyA-3-Tail. Unlike Picornaviridae and Flavidiridae, structural proteins found at the 3 end.

Virus enters via RME and replication of the Positive strand produces 1 Negative Strand which gives rise to 2 Positive Strands: Genome Size RNA (non-structural proteins) and a Subgenomic RNA (Structural proteins). Structural proteins are made in excess (thus excess Subgenomic RNA). Both RNAs form a polyprotein cleaved by a viral protease in the case of non-structural / Genomic RNA and a Host Protease in the case of Subgenomic / Structural RNA. Replication is entirely cytoplasmic with budding at plasma membrane. Nearly all mosquito transmitted.

I)

Eastern Equine Encephalitis (EEE)

Found in the eastern coastal states and Central and South America. Causes encephalitis in humans and is much more severe than the other types high mortality. Naturally cycles between birds and mosquitoes with humans and mice as accidental hosts. Actual cases may often undergo undiagnosed due to unapparent infections. No specific treatment.

II)

Western Equine Encephalitis (WEE)

Found in California, Prairie states, and Western Canada. Natural cycle is between birds and mosquitoes; humans and mice are accidental hosts. Causes encephalitis in humans but with a much better prognosis than other types. Prevention via vector control. No specific treatment.

III)

Venezuelan Equine Encephalitis (VEE)

Found in Central and South America, Mexico, and Texas. Causes Influenza-like Syndrome instead of encephalitis. Naturally cycles between rodents and mosquitoes; humans are accidental hosts. Prevention through vector control, and VEE Vaccine for humans. No specific treatment.

B) Rubivirus (Rubella)
Transmitted via Respiratory route NO arthropod vector. Rubella virus is the cause of German Measles or Rubella. Infection is benign, characterized by mild rash and minimal lymphadenopathy thus serology is best method for diagnosis. Importance in case of infected pregnant women (during Trimester 1) due to congenital cardiopulmonary, CNS, and eye abnormalities. Symptoms in children: cardiopulmonary problems, CNS problems (including eyes). In Adults: fever, rash, trunchal rash, and lymphadenopathy. Live attenuated vaccine available MMR Vaccine.

4) Caliciviridae
Small, spherical / Icosahedral, non-enveloped viruses. Single-stranded and non-segmented RNA with 3 ORFs (unlike Polios single). First ORF (5) encodes nonstructural proteins, second encodes a single capsid protein, third (3) uncertain. Common virus is Norwalk Virus; leads to acute gastroenteritis with vomiting and diarrhea. Disease is self-limited lasting 24-48 hrs. Affects mainly adults and school age children instead of infants (Rotavirus most widely infects infants). Replicates in the GI Tract and spread via Fecal-Oral Route. Prevention via: decontamination of food and water; hand washing. Hepatitis E Virus (HEV) has been placed in this group due to similar genome. HEV causes water-borne Hepatitis.

5) Coronaviridae
Large, spherical RNA viruses, Positive-Sense RNA; Largest RNA virus. Enveloped, with club-shaped glycoprotein spikes giving it a crown-like appearance (corona). RNA is capped, poly-adenylated and it is processed into 7 Subgenomic RNAs. Viruses bud at host-cytosolic membranes, not plasma membranes (between ER and Golgi). Commonly associated with gastroenteritis and common-cold syndrome, but now with Severe Acute Respiratory Syndrome (SARS). SARS may be confused with influenza but illness is far more severe with much higher mortality. Acute and severe fever (usually >100.4o F), severe cold-like symptoms with GI disturbances.

Negative Strand RNA Viruses

Enveloped via budding from plasma membrane. Surface glycoprotein spikes used for adherence. Mostly Single-stranded Negative Sense RNA. Non-structural proteins include Viral RNA Polymerases; structural proteins include nucleocapsid and M-Protein (Matrix). Glycoprotein Spikes adhere to cell, fusion occurs. Viral RNA polymerases make 2 types of Positive Transcripts: Primary single gene Transcripts made from Negative Strands (which encode structural and non-structural proteins); Secondary Transcript is a Positive Sense of the whole genome to be incorporated in new virions. New viral Glycoproteins accumulate at plasma membrane; virus released via budding. Many viruses in this group produce Viral Hemorrhagic Fever with symptoms such as: Acute Febrile Illness, Influenza- like, Petechial rash, ecchymosis, melena, thrombocytopenia, leukopenia, Hepatomegaly, and severe bleeding after venipuncture. There may also be the formation of large eosinophilic inclusion bodies, especially in the liver.

1) Orthomyxoviridae (Influenza Virus)

Two Envelope Glycoprotein spikes: Hemagglutinin (H) and Neuraminidase (N). H attaches to host cell sialic / neuraminic acid. N cleaves the bind between H and the sialic acid, thus freeing the virus from the host cell upon release. Matrix (M) Proteins confer stability to envelope. Nucleocapsid is helical with 8-different Negative Sense RNAs. Three major strands: Influenza A, Influenza B, and Influenza C. A and B are infectious for humans while C causes very rare infections. Virus types organized based on H and N antigens. Antibodies do not cross react. Viruses may spontaneously mutate via two mechanisms: Minor (Drift) mutations (single point mutations but serotype remains the same) are usually single-base pair and thus virus may require a new vaccine. Major (Shift) mutations result in new virus subtypes and may occur through recombination between different types (e.g. in animals that are co-infected with two serotypes simultaneously). Replication is not completely like other Negative Strand Viruses occurs instead in Nucleus since host pre- mRNA primers are needed for virus nucleocapsid replication. Starts with Virus removal of 5 caps from host transcripts, transcription of viral genes on these primers, and thus one mRNA per RNA segment. Influenza A is commonly spread via respiratory droplets and infection extent dependent on factors (i.e. smoking, local IgA levels, serum IgG, etc.). Disease includes acute onset throat and substernal pain, shortness of breath, cold-symptoms, non- productive cough, myalgia, fever, anorexia and lethargy. Pneumonias may be secondary. Two causes: 1) Secondary bacterial or 2) Virus itself.

Reyes Syndrome may develop in children and adolescents when taking excessive doses of aspirin acute hepatocerebral fatty infiltrates and degeneration. Pathology includes mucosal destruction via Neuraminidase (hydrolyzes mucous lining, destroying columnar cells) leading to impaired respiratory mucosal-clearance. Diagnosis made based on Viral Isolation via culture or growth on hen eggs, serology for Ab titers (paired), and Immunofluorescence of nasal secretions / sputum. Treat with supportive therapy including use of Oseltamivir and Zanamivir both neuraminidase inhibitors. Prevention via vaccination: Trivalent vaccine developed against two Type As and one Type B. Ab diminish within 6 months. Vaccination good for those who are at high risk: >50 years, Immunosuppressed, pregnant, Respiratory disorders, and healthcare workers. Nasal vaccine (Medimmune) is a cold-adapted live virus that grows best in the URT (cooler temperatures). Other drugs that are used include: Amantadine and Rimantidine prevents viral un-coating stops virus from de-enveloping and entering the host Cytosol. Influenza B also mutates via Major (shift) and Minor (drift) but less frequently. Children more susceptible and secondary sequellae more common such as Reyes Syndrome. Influenza C is rarely a clinical disease and not responsible for epidemics.

2) Paramyxoviridae
Enveloped, Non-segmented Negative Strand RNA Viruses. Helical Nucleocapsid. Instead of H and N, most have a HN Glycoprotein Spike which has both activities and is Major Antigenic determinant (exceptions: Morbilivirus which has no N and Pneumovirus which has no N or H). Also have an F Spike used in fusion and hemolysis activity this is characteristic of Parainfluenza infections). Common diagnosis via Syncytial (giant multi-nucleated) cell formations stained with eosin. Viral glycoprotein spikes leads to Syncytial formation. Paired serology, viral isolation via culture, and Immunofluorescence for viral RNA. Common disease includes respiratory illness. Normal individuals URT Infection with muco-ciliary nasopharyngeal epithelial damage. Severe cases include LRT infections with more destruction and hypoxemia. Young, elderly, and immunosuppressed patients at highest risk.

A) Para-influenza Virus (PIV) Types 1-4

LRT disease in young children. Older children and adults usually asymptomatic, less severity. Troublesome nosocomial infection and 2nd most common cause of LRT disease (after RSV). Disease includes LRT infection and also severe barking cough croup. Immunity to HN and F antibodies both necessary for prevention. Most adults have circulating IgG but serum IgG is not protective IgA is necessary since infection is on the RT. Those with T-cell deficiency can get Fatal Giant Cell Pneumonia. Four types. Pathology is via respiratory droplets but no viremia; limited to RT. Treat with supportative therapy including Ribavirin. Passive immunization via Ab administration. Childhood disease and many infections are asymptomatic. Capacity for widespread visceral invasion. Transmitted via saliva and other RT secretions close contact not necessary. Primary infection of URT, then lymph nodes, followed by salivary gland invasion. Shed in saliva prior to actual disease signs / symptoms.

B) Mumps Virus

Tissue damage in parotid gland from swelling and inflammation Parotitis = classic sign. Can spread to epithelia of various organs, regardless of parotitis. Gonadal involvement in 25% of all male cases; breast swelling in females. Vaccine = MMR. Unlike other Paramyxoviridae, has no Neuraminidase activity. One of the most infectious Childhood diseases and viable for hours in RT droplets. No animal reservoir spread via RT droplets. Disease with fever, sore throat, coryza, cough, conjunctivitis, followed by maculopapular rash (secondary phase; raised discolored spots). Primary Phase of URT or eye mucosal membranes then invasion of local epithelia and lymph nodes. Koplik Spots may appear on oral mucosa. Viremia results from macrophage / lymphocyte spread to lymph tissue, skin, kidneys, GI, and spleen. Secondary phase with intensified symptoms and maculopapular rash. Recovery occurs after rash begins. Immunity can be detected after rash begins (10-14 days after primary phase). Complications include secondary bacterial infections and Punctuate Keratitis. Subacute Sclerosing Panencephalitis (SSPE) may result rare progressive degeneration in neural tissue, primarily in 7-10 years old, route to CNS unknown, and marked by high Ab titers. Giant Cell Pneumonia may also occur due to surface Glycoproteins: mainly HA since no N spikes. Diagnosis CDC: generalized maculopapular rash, 3+ days, >101 F fever, cough, coryza, conjunctivitis. Treat with supportive therapy, Ig can be given to those in need. Prevent with MMR vaccine. No HN Spikes. Single most important cause of LRT Disease (Pneumonia and Bronchitis) in infants and children. Peaks at 2-7 months of age; mortality not common and premature at risk for chronic lung disease. Adults and older children may only get colds. Pathology via fomites, no viremia infection limited to RT. Viral shedding ends as IgA appears and thus indicates recovery. Immunity from IgA is more important than IgG. As IgA wanes, reinfection likely. Cumulative immunity from reinfection important in protecting adults and older children. Treat via supportive care, Ribavirin, no vaccine, RSV-Ig given Palivizumab (Monoclonal Ab via IM). Morphologically similar to RSV. Ubiquitous but does not culture well. Hendra virus jumps from fruit bats to horses to humans causing cases of fatal respiratory syndromes. Nipah virus transferred from pigs to humans resulting in human encephalitis fatalities, along with RT illness and CNS disease.

C) Measles Virus (Morbilivirus)

D) Respiratory Syncytial Virus (RVS) (Pneumovirus)

E) Human Metapneumovirus

F) Hendra and Nipah Viruses

Both Hendra and Nipah viruses are antigenically cross-reactive but not with other Paramyxoviruses. In other respects (morphology and genome arrangement) are similar to Paramyxoviruses.

3) Rhabdoviridae
Contains two genera: Rabies and Vesicular Stomatitis Virus (a rare asymptomatic or mild disease). Bullet shaped with Glycoprotein spikes (G) which is major Antigenic determinant and Neutralization site. Helical nucleocapsid contains one Single Stranded Negative Sense RNA.

A) Rabies Virus
Major vectors include dogs while major reservoirs include skunks, foxes, wolves, and bats. Three phases of disease: Prodromal Nonspecific symptoms like fever, chills, headache, photophobia, and numbness at bite site. Acute Neurological Nervous System dysfunction like anxiety, agitation, delirium, hydrophobia and throat muscle spasms. Coma Death due to respiratory arrest. Pathology includes infectious saliva via lick to open wound. Then an incubation of 1-2 months progression dependent on bite proximity to CNS. Virus then replicates in bite site tissue. Then movement to PNS by replication in neurons (retrograde). Virus moves to brain and then other organ systems. Final phase includes invasion of submaxillary glands (has highest titer). Within the CNS, Negri Bodies may be present; these are encephalitic CNS lesions. Diagnosis made through clinical history of exposure and Fluorescence Ab to Viral Antigens (unfortunately, postmortem usually). Symptoms alone can confirm disease only once neurological signs appear. Treat usually only with post-exposure prophylaxis. Once disease becomes clinical (neurological), no successful treatment. If animal is known, retain animal and once animal shows symptoms, kill and check brain samples (progresses faster in animals than humans). Multiple doses of Rabies Vaccine can also be given Human Diploid Cell Culture killed vaccine. Anti-rabies Ig (human or equine) can also be given Human Rabies Ig (HRIG).

4) Arenaviridae
Encapsidation of host ribosome gives virus sandy appearance in EM. Nucleocapsid has 2 Spikes GP1 and GP2. GP1 interacts with host cell receptors while GP2 facilitates acid- dependent fusion out of from endosome to Cytosol. Single-Stranded Negative Sense RNA is bi-segmented. Genome is considered Ambisense thus some genes go from Negative Sense > Positive Sense > mRNA > Protein, while others go Negative Sense > mRNA > Protein. Pathology: a chronic asymptomatic infection of rodent hosts (reservoir). Virus then spreads via rodent excreta to humans. Humans may excrete virus in urine and semen for weeks after recovery. Disease includes viral hemorrhagic fevers (see above) with person-to-person spread via body fluids. Treat via Ribavirin (but does not penetrate CSF) and Convalescent plasma prophylaxis for those exposed.

A) Lymphocytic Choriomeningitis (LCM) Virus

Reservoir = Hamsters and Mice. Prodrome includes flu-like symptoms but 10 days later, meningeal symptoms may result, but CNS involvement is rare. No Person-to-Person spread. Hemorrhagic disease with multiple organ involvement.

B) Lassa Fever Virus

Deafness may persist after recovery. Newly emergent reservoir is rats.

C) Whitewater Arroyo Virus (California)

5) Bunyaviridae
Consists of several genera which cause human diseases. Surface glycoprotein Spikes are G1 and G2. RNA has 3 segments: L (polymerase), M (G1 & G2), and S (N Protein). Each is compromised of individual nucleocapsids. Each Virion may have a variable number of nucleocapsids (leading to size variability). RNAs have complimentary termini and thus may appear circular. Primary mRNA need cellular RNA primers from old host cytosolic mRNAs (unlike Orthomyxoviruses). In some, for the S RNA segment, 5 end is Ambisense.

A) Bunyavirus
California Encephalitis Serogroup La Crosse virus leading to febrile illness with encephalitis. Spread via mosquito vectors from rodent reservoirs. Crimean-Congo Hemorrhagic Fever Virus spread via Tick Vector and hosts are mammals. Hemorrhagic fever with Person-to-Person spread possible (nosocomial). Two major types: Rift Valley Fever Virus (RVF) and Sandfly Fever Virus (SFV). RVF spread via mosquito and hosts include domestic animals. Produces influenza-like disease in humans with hepatitis, encephalitis, and retinitis. Transmission possible via contact with tissue or blood. SFV Spread via Sandfly and produces non-fatal influenza-like illness. Three major types: Hantaan Virus, Korean Hemorrhagic Fever, and Sin Nombre Virus. Hantaan Virus: Hosts are rodents and human infection via rodent excreta. Produces hemorrhagic fever with renal syndrome (likely in farmers). No person-to-person spread. Korean Hemorrhagic Fever Virus: produces hemorrhagic fever with renal syndrome. Sin Nombre Virus (Hantavirus Pulmonary Syndrome): Found in the SW USA and spread via Deer Mouse. Produces severe cardiopulmonary illness in healthy young adults with rapid progression. Respiratory failure may result.

B) Nairovirus

C) Phlebovirus

D) Hantavirus

6) Filoviridae
Pleomorphic, long filaments = branched, U-Shaped, or 6-Shaped. One Single-Stranded Negative Sense RNA. Spread from animals to humans most likely. Disease includes Viral Hemorrhagic Fevers (see above). Pathology includes Highly Virulent Strains such as Marburg-Ebola and Zaire-Ebola and less virulent strains such as Sudan-Ebola and Reston-Ebola. Extent of transmission and details on infection are not known. However patients develop hemorrhagic fever. Patient also has a high degree of viremia. Likely spread via aerosol, person-to-person infection and sharing / reusing needles. Diagnosis made as part of differential for any acute febrile illness after travel to rural Africa. The tip-off is person-to-person transmission. Lab tests include Virus isolation from Blood and Postmortem tissue (send to CDC) and Serology for Ab. No specific treatment but supportive care. Must isolate patients with barrier nursing techniques.

Double-Stranded RNA Viruses

All viruses have double-stranded RNA.

1) Reoviridae
Older name of this family is Respiratory Enteric Orphan Virus (REOV) Four genera: Reovirus, Orbivirus, Rotavirus, and Coltivirus Icosahedral shape, non-enveloped, with a Double-Protein Capsid (outer and inner). Outer capsid proteins are antigens. Have 10-12 segments of dsRNA of which each are transcribed into mRNA with 1-2 ORFs. Replication begins with attachment to sialic acid (receptor) and outer capsid acid-degraded (via endosome) upon entry. Innercapsid is now called Subviral Particle (SVP). Inner core has dsRNA from which a Positive Strand is created and released into Cytosol and is replicated into many copies. Viral Proteins made using host machinery. ssRNAs associate with virion proteins and new virions are formed. ssRNA is turned to dsRNA within new virion. dsRNA is never released into Cytosol since it is a flag for host immune response mainly interferon- gamma. Infection also inhibits host protein and DNA biosynthesis. Lysis of cell allows for virions to be released no envelope needed.

A) Reovirus
RT and Enteric Virus. Ubiquitous: river water, stagnant water, and sewage. Most common diarrheal pathogen in children worldwide Infects Intestinal Mucosa. Range from watery diarrhea to severe dehydration to vomiting and fever. Major cause in childhood deaths and has an incidence peak in 4-36 months of age; also nosocomial. Subsequent infections lead to more immunity since IgA is protective (cumulative immunity) in the Intestinal Lumen. Fecal-oral transmission likely shed in diarrhea and RT secretions. Treat with supportive therapy (hydration; IV if serious). Vaccines developed in 98, 06, and 08. 98 vaccine led to Intussusceptions (bowel obstructions). 06 vaccine was redundant (for 5 Strains) while 08 was for only one strain due to cross-antigenicity of most strains. Gamma globulin may also be given to patients. Transmitted via tick bite. Leads to mild non-specific illness usually without rash. Virus replicates in RBCs and thus escapes Ab. Can cause Leukopenia and Thrombocytopenia. Severe CNS disorders, hemorrhagic fever, and GI bleeding may also result. Treatment only if symptomatic.

B) Rotavirus

C) Colorado Tick Fever Virus

DNA Viruses
Range in size from the largest to smallest human viruses. All are cytopathic and nearly all replication in the host cell nucleus (except for the Poxviruses). Some encode proteins to cause cell division and block apoptosis in host cells.

1) Poxviruses
Largest and most complex. Replicates in the cytoplasm unlike other DNA Viruses and encodes genes derived from host. Human pathogens: Smallpox (Variola), Molluscum Contagious Virus, Livestock-Poxviruses, and Monkeypox. Morphology: Brick-shaped on EM with an envelope that has ridge-pattern. DNA core is concave with to lateral bodies flanking. Replication: Within the Cytoplasm unlike all other DNA viruses. Occurs inside of cytoplasmic inclusions called Guarnieri Bodies (virus factory). Early mRNAs transcribed within core which has viral RNA Pol, capping enzymes, and other needed factors. The proteins of these mRNAs are Early Proteins needed for the release of the Viral DNA from the core and DNA replication. DNA replication leads to Late Proteins which are those incorporated into new virions. Have genes homologous to host immune-system genes which can function to block host immune function. Highly Contagious Spread via the RT and fomites. Initial URT infection results in viremia which seeds into the RES, then macrophages, and finally systemic. Prior to rash, fever and malaise occur. Lesions of the oral cavity rapidly ulcerate and then skin lesions evolve from macules, to papules, to vesicles, to pustules which scab over and ultimately heal. Viruses present in lesions and lesions have dermal necrosis. Two forms: Major (Bedridden) and Minor (Ambulatory) Minor is a public health risk (patient = vector). Recovery yields lifelong immunity. Procedure for vaccine includes multiple pricks after application of Vaccinia Virus (vaccine virus). Diagnosis: Pox distributed on face and extremities and then on trunk (Varicella is the opposite). Lesions appear in the same stage of development (unlike Varicella). Lab tests of vesicle fluid, EM, Virus Isolation, serology for Ab or Antigens, and PCR for Viral DNA. Treat with Methisazone for prophylaxis prior to the appearance of symptoms. Vaccinia Ig can be given if patient develops reaction / illness from Vaccinia Virus. Infects only humans leading to non-malignant skin tumors. Scratching of wart-like lesions may lead to autoinoculation thus increasing lesion numbers. Lead to single lesions on the hands. Occur in those who work with livestock. Similar to Smallpox except less lethal. Includes systemic febrile illness and vesicular skin lesions.

A) Smallpox

B) Molluscum Contagiousum Virus

C) Poxviruses of Livestock

D) Monkeypox

2) Parvoviruses
Smallest human viruses; Icosahedral, non-enveloped with Negative Sense ssDNA.

Encodes only 1 capsid protein and 1 nonstructural protein needed for replication which takes place in the host cell nucleus using host-cell proteins. Major Pathogen is Parvovirus B19 which is transmitted via three major routes: 1) Blood Transfusion, 2) Mother-Fetus, and 3) RT Route. Disease is in bone marrow RBC Lineage Cells. RBC production ceases for about 1 week for persons with normal RBC turnover. For those with hematological disorders or immunosuppresion (Sickle-Cell and others), transient aplastic crisis may occur or progress to Pure Red Cell aplasia. Other complications: Erythema Infectiousum (5ths disease) may result in children slapped cheek rash, lacy red rash trunk and limbs, and anti-B19 Ab. Rash is deposition of Immune Complexes and such complex deposition in adults may lead to arthritis. Maternal-Fetal route can result in serious disease of fetus. Diagnosis is usually on serological grounds after clinical picture difficult to culture. Most do not require treatment. If needed, treat with blood transfusions for aplasia, IV Ig with anti-B19. Other Parvoviruses are Adeno-Associated viruses with replicate inside of cells infected with Herpes or Adenoviruses but not linked to any specific illness. dsRNA Genomes, non-enveloped icosahedral nucleocapsids. Small genomes: have 8-10 genes. Replicate in host-cell nucleus using host machinery. Three prototype members: Papilloma Viruses, Polyoma Viruses, and Simian Vacuolating Virus-40 (SV40). Drive cells into continuous division. Attack terminally differentiating epithelial cells thus primarily skin and mucosal membranes. Cores of lesions consists cells dividing under viral control. Use host-cell machinery for replication. Replication involves 10 proteins: 8 Early Proteins and 2 Late Proteins. Individual proteins made from differential splicing (many genes overlap). Early Proteins include E6 and E7 (along with others), while Late Proteins include L1 and L2. E6 blocks apoptosis by modifying the Ubiquitin Protein-Ligase to ubiquinate p53 for proteolysis. This prevents p21 (p53s target) from inhibiting division. Meanwhile, E7 binds to Retinoblastoma Protein (Rb) thus freeing E2F from inhibition. This leads E2F to promote division. L1 is the Capsid Protein. Virus replication cycle requires differentiation of cells: 1) Basal Stem Cells Early Proteins made in small amounts, 2) Supra-Basal Cells Early Proteins made in large amounts, E1 & E2 activate viral DNA replication, 3) Highly Differentiated Cells Late Proteins made and new virions assembled, host-cell killed. Prevalence is high and infection is major risk factor for cervical cancers + other genital cancers. Productive infection kills infected cells while Non-Productive infection leads to tumor formation (if viral genes get incorporated into Host-Cell DNA). Two major types associated with cancer: Types 16 and 18. Treatment involves a combination of the following: surgical removal of infected material, liquid nitrogen or cytotoxic drugs to kill infected cells, and interferon (in cases of genital warts or laryngeal papillomas). Prevention with HPV Vaccine composed of Type 16 and 18 L1 protein (empty capsids). Ubiquitous but cause illness only in the immunocompromised types: JC and BK Viruses. Inhibit p53 and Rb via a single Early Protein called T-antigen (T for Transformation).

3) Papovaviruses

A) Human Papilloma Viruses

B) Polyomaviruses

Disease includes Progressive Multifocal Leukoencephalopathy (demyelinating disease) killing Oligodendrocytes. Has historical significance with Poliovirus (Polio grown on SV40 contaminated Lab media).

C) SV40

4) Adenoviruses
First isolated from adenoidal tissue. Icosahedral nucleocapsid with long protein spikes which mediate cell-attachment. Drive cell division via E1A (Rb inhibition) and E1B (p53 inhibition). Also other Early Proteins inhibit cell Class 1 MHC expression, suppress interferon response, and prevent TNF-induced apoptosis. Infections result from killing of epithelia cells of the RT, GI, and Urinary Tracts along with cornea / conjunctiva infection. Transmission is via the fecal-oral and RT routes. Illnesses produced include Acute Febrile RT Disease and pneumonia in children and young adults, Pharyngeoconjunctival Fever with inflammation, and Gastroenteritis (notice all membrane-epithelial). Oral live vaccine available which multiples in the GI tract leading to immunity. 3 Subfamilies: Alphaviruses (HSV1, HSV2, VZV), Betaviruses (CMV, HS6, HS7), and Gammaviruses (HS8, EBV). Morphology: Core with linear dsDNA, Capsid is Icosahedral, between Capsid and Envelope is an amorphic Tegument with viral proteins and viral mRNAs. Envelope is lipoprotein sensitive, derived from host cell nuclear membrane, with Glycoprotein Spikes, and is impermeable to stains. All Herpesviruses are structurally similar. Viral genomes encode enzymes for: Nucleic Acid, DNA, and Protein metabolism. Synthesis of virions in nucleus. Productive forms can kill cells. Viruses may remain latent in host leading to acute-recurrence. Vary in terms of host range, multiplication, destruction speed, latency cell type, and clinical disease. Replication for all is similar: Attachment > Fusion > Tegument protein release (Virion Host Shutoff and alpha-Transinducing Factor) > VHS shuts of Host Cell Protein Synthesis > Capsid goes to nucleus via nuclear pore > Viral DNA enters > alpha-TIF initiates Immediate Early (IE) Proteins > IE proteins translated in cytoplasm, return to activate Delayed Early (DE) Proteins (Viral Thymidine Kinase + Viral DNA Pol) Synthesis > DE made in Cytoplasm, returns to activate Late Proteins (structural) > Assembly of new virion capsids, bud from nuclear membrane > Move to ER and then ECM (highly inefficient) > immediate attachment to adjacent cells. Replication of viral proteins is rolling-circle; late in the infection, Late Proteins shut off IE and DE proteins. Some Herpesviruses produce cytokine inhibiting proteins which are homologs; they block receptors. Some also use mechanisms to block MHC 1 Expression by: blocking the MHC 1 chains in the ER, dislocating MHC 1 chains and redirecting to proteosomes, inhibit peptide transfer to MHC 1, sending new MHC 1 to endolysosomes, and promoting MHC Endocytosis and degradation. Also produce Interferon (INF) homologs which inhibit natural Interferon synthesis / activity. Both HSV1 and HSV2 are closely related; are quick and destructive with short life-cycles.

5) Herpesviruses

A) Herpes Simplex Virus 1 and 2

HSV1 is primarily responsible for Herpetic Gingivostomatitis (core sores, etc), Herpetic Keratoconjunctivitis, and Herpes Simplex Encephalitis (in immunosuppressed patients and infants) primarily due to inadequate cellular immunity. HSV2 is primarily responsible for Genital Herpes and Neonatal Herpes. Transmission: HSV1 = Oral-Oral, Oral-Genital, and HSV2 = Primarily Genital-Genital. Virus replicates locally, and spreads via supporting axons and nerves. Latent infection in ganglia. Pathology of Host Cells includes focal necrosis, and multinuclear giant cells. Since virus spreads cell-to-cell, its only seen during initial infection. Latent infections persist in ganglia adjacent to initial site. But no replication or necrosis. Virus avoids immune detection since infected cells usually dont express MHC 1 escape CTLs. Latency Associated Transcripts (LATS) produced which inhibit viral replication via ICPO Gene. Recurrence is common during high stress times; travel along axons shorter duration. If infected with one type, other types infection will be less severe. Diagnosis made on the basis of lesion scrapings looking for Multinucleated Giant Cells, viral culture for destruction patterns, and fluorescence antisera to early viral proteins. Prevention through cautious sex and cesarean sections during delivery of infectious mother. Treat with Acyclovir but it does not prevent latency and some may become resistant. Also, Foscarnet may be used its a Viral DNA Pol inhibitor. Viruses include Chickenpox and Shingles both are immunologically identical. Spread via RT or Direct Contact of pustules; high titer in vesicle fluid. Pathology includes Systemic disease: RT entry with local multiplication, then to regional lymph nodes, next viremia, followed by hepatospleno manifestation and skin infection. Spread accomplished via circulating Lymphocytes. Presentation: fever, malaise, and rash on the following day. Rash in waves; not painful; spreads trunk to face + extremities, and goes vesicles to papules and crusts over. All forms of rash simultaneously. Most infective 24-48 hr prior to rash; no shedding in asymptomatic cases. Latency of virus in multiple sensory ganglia usually trigeminal and dorsal root. Complications that may result include bacterial super infections / Pneumonia, Neurological disorders with meningoencephalitis, and birth defects. Recurrent infection: Shingles (Herpes Zoster). Inflammation and vesicles along affected nerve. Usually only one ganglion affected in each recurrence rash lasts 2-4 weeks, pain lasts for months. Prevention: Live-attenuated Varicella Vaccine for those > 1 yr of age. Prophylaxis: Ig 72 hrs post exposure. Treat with Acyclovir must be IV. Famciclovir is similar and can also be used. Major complication in Organ Transplants due to immunosuppresion. Asymptomatic infection common to adolescence, salivary disease of newborns leading from viral shedding of mother. Can cause severe congenital abnormalities: motor / mental retardation and hearing loss. Retinitis may occur in late stage AIDS and mononucleosis-type (EBV) disease. Pathology: does not kill cells, cytomegaly with nuclear inclusion bodies. Infects epithelia and leukocytes thus potential for systemic spread. Latency: Neutrophils and Monocytes; mechanism of latency not dependent on viral protein or vRNA. Prevention: check donated blood, safe-sex, and Ab for transplant patients.

B) Varicella-Zoster Virus

C) Cytomegalovirus

Treat with Ganciclovir (like Acyclovir but different kinase) Acyclovir does not work; no viral Thymidine Kinase. Causes Infectious Mononucleosis, affecting lymph system and splenomegaly. Spreads via Saliva thus children and teens mostly exposed (kissing disease). Lasts for weeks. Incidence associated with tumors: Burkitts Lymphoma and Nasopharyngeal Carcinomas. Pathology includes infection of the mouth mucosa, then regional lymph node spread, infection of B Cells but not cell death, B Cells proliferate leading to Heterophilic Antibodies (Polyclonal), also viral Antigens expressed on B Cells, thus CTLs activated (called Atypical Lymphocytosis). CTLs keep B Cell population size in check. Targets B-Cells and CTLs in response are called Downy cells due to a foamy appearance. Without Downy Cells, B-Cells would proliferate and produce Lymphomas and thus CTLs are present in higher-than-normal concentrations. In Latency, EBV expresses viral genes and may have non-translated RNAs like HSV LATS. These viral genes include: 1) EBVNA1-3, which maintains vDNA as a plasmid, is necessary for B-Cell Transformation and also inhibits MHC 1 presentation, 2) LMP1-2, acts as an Oncogene leading to growth, prevents apoptosis and stops reactivation from latency, 3) EBER which are RNAs involved in apoptosis resistance. Diagnosis based on the presence of Downy Cells, serology for Ab to Capsid (VCA Viral Capsid Antigen) and EBV Nuclear Antigens (EBVNA). Anti-VCA Ab present early and indicate an acute infection, while Anti-EBVNA present later and indicate past infection. Also, Polyclonal Ab spike in serum may be seen. Treat with Acyclovir to reduce replication; mostly self-limiting; watch out for spleen rupturing. Common to 6 months 4 years old. Causes Roseola Infantum (6ths disease) in infants / children, and severe encephalitis, meningitis, interstitial pneumonia, hepatitis or retinitis in immunosuppressed / AIDS patients. Transmitted via oral or cervical secretions (newborns and STDs). Pathology involves Salivary Gland Replication, then Monocytes / Lymphocytes infected (cells with CD4+ primarily), may induce CD4+ expression on other lymphocytes, and Large multi-nucleated cells. Latent Infection in T-Cells but no cell transformation. Diagnosis based on clinical course in infants. Disease has initial 2-3 days fever followed by macular rash for 1-3 days, which then spontaneously resolves. Treat with Ganciclovir (more responsive than Acyclovir). Also may use Foscarnet in immunosuppressed patients. But disease is normally self-limiting. Common; most adults have Ab. 50%-60% related to HV6 and prefers CD4+ Cells. No evidence for involvement in Human Disease. Associated with Lymphoproliferative disorders. Kaposis Sarcoma Herpesvirus (KSHV) multiple pigmented skin sarcomas with four major forms: Older European men, Equatorial Males, Organ Transplant Patients, and HIV-1. Not ubiquitous . Primary Effusion Lymphomas (body cavity Lymphomas) may also result. Multi-focal Castlemans Disease Rare Lymphoproliferative disorder related to immune dysregulation. May also be related to Multiple Myelomas since virus induces B-Cell Proliferation also since Virus encodes for Chemokine Homologs, thus CTL and T-Helper Activation suppressed.

D) Epstein-Barr Virus (EBV)

E) Herpesviruses 6

F) Herpesvirus 7

G) Herpesvirus 8

Thought to be a STD. Treat with surgery for single lesions and in cases of Multifocal Lesions, radiation and / or chemotherapy may be used. Ganciclovir, Foscarnet, and Cidofovir may also work by inhibiting replication and KS Lesions.

Retroviruses Viruses
Retroviruses are RNA viruses that replicate via a DNA intermediate. They integrate their genome into the genome of permissive cells to form a provirus. The hallmark is Reverse Transcription in which there is a reverse flow of information: RNA to DNA. They measure about 100 nm in diameter and have a lipid envelope with spikes. All infectious mature virions contain a condensed core. The core usually consists of two identical ssRNA Positive Sense strands. The process of infection is similar across the Retrovirus family. The general process is as follows: Initiated with Surface Envelope Protein (SU) binds to the corresponding receptor. Fusion occurs and Capsid / Core enters cell. The Core comes off and the viral RNA genome is reverse transcribed into DNA with the viral Reverse Transcriptase. This involves a two-strand transfers which add on a U3 region to the R-U5 end and add on a U5 to the U3-R end. This, now, Viral DNA is bound to Integrase (IN) and the Pre-Integration Complex is formed. In some Retroviruses, the integration of Viral DNA into the cell genome may require a mitotic cell state (not with HIV). The IN-Viral DNA Complex (Pre-integration) is integrated into the host cell genome via sticky ends. The viral genome, once integrated into the host genome, is transcribed by host RNA Pol II. This produces a minimum of 2 mRNAs. One is a full-length transcript leading to the GAG or GAG-POL polyprotein and may also be incorporated into new virions, while the second is an mRNA that is spliced once leading to the ENV Polyprotein. The GAG or GAG-POL is transported to the cytosolic / inner cell membrane area. The ENV Polyprotein has a Signal Peptide (SP) at one end which anchors it to the ER membrane. The rest of the polyprotein is cleaved into the Surface Subunit (SU) and the Transmembrane Subunit (TM) which together forms envelope spikes. ENV cleavage is carried out by a cellular protease while GAG or GAG-POL is via the viral protease. The ENV proteins are then embedded into the cellular inner membrane and the GAG or GAG-POL proteins meet them to assemble the new virions. New Virions then bud off. At this point, new virions are immature meaning that their inner core is not assembled. As the immature virion buds off, an inner protease cleaves the GAG or GAG-POL Polyproteins. The GAG or GAG-POL Polyprotein is cleaved into: Matrix (M), Capsid (CA), Nucleocapsid (NC), Protease (PR), Reverse Transcriptase (RT), and Integrase proteins (IN). GAG-POL gives rise to all of them while GAG only gives rise to the first 3. The new virions are now mature and infectious.