Bugs

Viruses

HIV.

A retrovirus whose virion contains two SS copies of the genome, reverse transcriptase, protease and integrase in a capsid and envelope containing gp120 and gp41. gp120 binds to CD4 found on CD4+ T cells, macrophages and dendritic cells. The resulting conformational change in gp120 causes gp41 to mediate fusion. gp120 contains frequently mutating hypervariable regions, preventing antibody specificity. The high mutation rate of HIV is due to the two error prone RNA transcriptase steps. Virion forms in cytoplasm, buds via cell membane. Humans are the only hosts, transmission is through sex and infected blood. The dose needed for infection is high. Three stages: 1. 2-4 weeks after infection, acute (fever, lethargy, sore throat, lymphadenopathy, rash on trunks and legs) with normal CD4 resolving in 2 weeks; 2. Asymptomatic, latent 7-11 years; 3. Late, immunodeficiency (AIDS) due to CD4 sub 400/microL, increase in opportunistic infections etc., most commonly pneumocystis pneumonia, Kaposi's sarcoma, herpes simplex, zoster, CMV, thrush, tuberculosis, meningitis along with neurological problems. Other cells with CD4 (dendritic cells, macrophages) also infected. Immune response through CTL activation ineffective and gradually gets worse due to their not receiving cytokine signals because of low CD4+ T cells. Treatment is with HAART: two reverse transcriptase inhibitors (zidovudine and nevirapine) and a protease inhibitor (saquinivir). No vaccine - prevention is through antiretrovirals at birth, C section, avoidance of breast feeding, safe sex.

Influenza.

An enveloped, 100nm orthomyxovirus causing global epidemics every 10-20 years (A), major outbreaks every year (B) and mild respiratory tract infections (C). Contains a segmented, single stand negative sense RNA genome and an envelope with spikes of haemagluttinin (binds the cell surface receptor sialic acid, mediating entry) and neuraminidase (cleaves sialic acid, allowing progeny release). The virus enters the cell in vesicles and uncoats within the endosome; the RNA polymerase transcribes the 8 genome segments in the into mRNA in the nucleus. The capsid then is translated and assembled in the cytoplasm around ribonucleoproteins and released through budding. Influenza is cytopathic as a result of damage to cell machinery during replication. Immune evasion: antigenic shift (only flu A) through reassortment of genome segments between species, e.g. in pigs (due to cells being infected with multiple strains); and antigenic drift, occurring through mutations during error prone transcription. 24-48 hr incubation, symptoms are acute fever, myalgia, sore throat, cough. Immune response is primarily through interferon response to dsDNA and CTLs; protective immunity through non-strain-specific IgA secreted onto respiratory tract. Neuranimiase degrades protective mucus layer for access to upper/lower respiratory tract, where infection is limited to despite systemic symptoms (due to cytokines). Complications are pneumonia (esp SA) and in children, Reye's disease. Treatment is with amantadine, preventing viral entry from endosome to cytoplasm and zanamivir, inhibiting neuranimidase but both are limited because they must be given early. Vaccines for A (H1N1 and H3N2) and B (1) reformulated each year.

Polio

A 20-30 nm picornavirus, non-enveloped and with icosahedral nucleocapsids and a single stranded, positive polarity linear RNA genome. Transmitted through the faeco-oral route, initially infecting gut epithelium with a 10-14 day incubation. Entry mediated through binding of capsid to poliovirus receptor on cell surface, inducing a conformational change allowing entry of viral genome, which functions as mRNA and is translated into a large polypeptide and cleaved by viral protease to produce needed RNA. Genome replication is by synthesis of negative complementary strand which acts as a template for positive sense new strands. Assembly is by coating RNA with proteins; virions accumulate in cytoplasm and are released upon cell death. Most infections are restricted to the gut but spread to spinal cord neurons leads to flaccid paralysis of muscles and permanent nerve damage. Specific symptoms include neck stiffness, respiratory paralysis, meningitis with fever. Treatment is by symptom relief; two vaccines (inactivated, Salk and activated, Sabin) are effective due to the antigenic stability.

Hepatitis

Hep B is a highly transmissible hepadnavirus containing a partly double stranded circular DNA genome and an envelope with a genetically stable surface antigen protein (HBsAg) produced in excess during infection (a diagnostic marker). Transmission is through blood, sex and childbirth. Virus infects hepatocytes through a specific cell receptor and replication is restricted to liver. Symptoms include fever, anorexia, vomiting, jaundice, dark urine, pale faeces. Entry is by binding cell surface, synthesis of missing portion of DNA to form circular genome and then mRNA using cellular RNA polymerase and a template of the viral genome. Progeny HBV with HBsAg coat are released through budding, non-cytopathically. Viral infection is controlled by CTLs that mediate killing infected hepatocytes, with a long incubation period of 4-20 weeks; HBV is not hepatotoxic - damage is from immune response leading to hepatocellular carcinoma. 5% become chronic carriers, especially if CTL escape mutants, MHC alleles, virus strain variation and clonal exhaustion are present. Generated antibodies provide lifelong protection. Treatment is with INF-alpha and Adefovir (reverse transcriptase inhibitor). Prevention is through HBsAg vaccine. Hep A (faeco-oral) and C (blood) and others exist.

Epstein-Barr virus

Causative agent of mononucleosis and Burkitt's lymphoma/nasopharyngeal carcinoma, a 120-200 nm encapsulated herpesvirus with a linear dsDNA genome transmitted mainly through saliva. Entry is mediated by glycoprotein gp340 binding to CR3 complement on B cells and uptake in a vesicle is followed by genome entry due to fusion of the vesicle with viral envelope, setting up a latent infection in B cells. Replication relies on transcription of the DNA genome by host RNA polymerase. The genome contains many proteins that subvert the immune system. EBV has latent and lytic modes of replication. Symptoms are fever, sore throat, lymphadenopathy, anorexia and fatigue with recovery in 2-3 weeks. Associated with cancers of lymphoid origin (Burkitt's in Africans, nasopharyngeal cancer in Chinese and thymus in the USA). Immune response is through CTL killing infected B cells, with antibodies produced against capsid antigen. No effective therapy (Aciclovir in high doses if life threatening) and no vaccine.


Bacteria

Strep pyogenes

G+ strep group A skin commensal found in chains or pairs; causing pharyngitis, cellulitis, rheumatic fever, acute glomerulonephritis. Causes disease through local pyogenic inflammation, toxin production and immuno cross reaction (RF and GN) Spread through resp droplets; diagnosis through haemolysis on blood agar (alpha- incomplete, produce green zone, beta- complete, clear zone, gamma- no lysis). For suppurative infection, bug produces hyaluronidase (breaks down subcutaneous matrix in cellulitis), streptokinase (facilitates blood clot breakdown by activating plasmin) and DNAase (inflammation). Erythrogenic toxin causes rash in scarlet fever, pyogenic exotoxin A is superantigen causing toxic shock, streptolysin causes beta-haemolysisn and exotoxin B degrades tissue in necrotising fasciitis. Post-streptococcal disease can occur due to antibody cross-reactivity but usually recovery is within 10 days. Treatment with pennicilin (and flucloxicillin for cellulitis of unknown origin).

Staph aureus

G+ cocci clusters causing abscesses, pyogenic infections of surgical wounds and burns, food poisoning, toxic shock, sepsis, pneumonia and endocarditis. Diagnosis is through G+ cocci in clusters, yellow/gold colonies on blood agar, coagulase + (staph epidermis is -ve) or catalase +. Found on skin and on 5% of vaginas (predisposing to TSST) and transmitted via hands.


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