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Viral Pathogenesis Early association of viral diseases with unique or distinctive signs/symptoms Poliomyelitis (paralysis) Rabies (illness following bite by rabid dog) Smallpox (characteristic fever/rash) Early theories of “contagion” Viral epidemics Clues point to a single transmissible agent Evolution (“natural history”) of the infectious process observed Measles Measles infection was distinguished from smallpox as early as the 9th century by an Arab physician by the name of Abu Becr (or Rhazes of Baghdad). However, there is no record of repeated epidemics identified as measles until the 11th and 12th centuries. Measles was first mentioned as a childhood disease in 1224. The Danish physician Peter Panum is generally given credit for illuminating the basic principles of measles infection and epidemiology during his trip to the Faroe Islands in 1846 during a measles epidemic. Measles Epidemic (P. L. Panum. (1847). Observations made during the epidemic of measles on the faroe Islands in the year 1846. Bibliothek for Laeger, Copenhagen, 3R, I: 270-344. 1846, Faroe Islands (North Atlantic) Population 7,900 “Patient Zero”: from Copenhagen Arrived March 28, developed measles early April By October: 6,000 cases of measles 170 deaths Inferences from Clinical Observations of the Measles Epidemic Transmission by direct person to person contact Consistent signs & symptoms Patient was contagious at onset of disease symptoms Febrile rash associated with viral shedding Differential mortality n Distinct agent involved for each transmissible disease Interval btw exposure & disease ~ 2 weeks measles was caused by a specific agent purely contagious, not miasmic-borne; isolation is best Rx Variable host responses to single infectious agent Immunity Disease does not appear n twice in the same person Long lived (65 years) Establishment of the Germ theory (18th, 19th century) 1850, Semmelweiss 1857, Pasteur different fermentations associated with different microbial agents each infection caused by a specific agent 1867, Lister “child-bed fever” (streptococcal infections) in OB-GYN ward spread by physicians due to failure to wash hands between examining patients Carbolic acid (antiseptic) can reduce post-operative infections 1865, anthrax bacillus cultured 1877, anthrax experimentally transmitted 1881-1884, Koch postulates formulated Henle-Koch Postulates (1884) The incriminating agent can be cultured from lesions of the disease The agent can be grown in pure culture The agent reproduces the disease when introduced into an appropriate host The agent can be recultured from the disease host Road to Virology “Contagium vivium fluidum” Beijerinck, 1898 QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. Proved that the mosiac disease of tobacco plants (now known to be caused by TMV) can be transmitted by extracts of infected leaves--"contagious living fluid” Extracts were still infectious even after filtration through procelain filters (which can sterilely remove all known bacteria at the time) No bacteria can be cultured from this fluid by known bacterialogical techniques Road to Virology “such a minute living being” Loeffler and Frosch, 1898, characterized transmissible agent of foot-and-mouth disease Obtained infectious fluid from alcohol-sterilized vesicles (free from contaminating skin bacteria) Proved that causal agent was in filtered lymph of infected animals, but was “unculturable” and microscopically invisible Serial dilutions indicate that causal agent was active in greater than one part in 1017--must be replicating agent Suggested that causal agents of smallpox, measles, cowpox might also belong to the same class of “minute living beings” Road to Virology Yellow fever (first demonstration of a transmissible viral disease in humans, 1900) Mosquito transmission Infected Beddings Mosquito Screens “Volunteer soldiers” + - + - Developed Yellow Fever Road to Virology Yellow fever (first demonstration of a transmissible viral disease) Serum transmission “Volunteer soldiers” Injected with serum from patients with acute yellow fever Serum was filtered through bacteria-excluding filters IRB Approval ??!! Not!!! Viral Pathogenesis: the early years 1900-1950 No cell culture system, no titration method 1908, poliovirus passaged to monkeys by intracerebral innoculation of spinal cord homegenate from acutely fatal human case 1910-1913 Neuro-adapatation Peyton Rous, tumors in chickens can be passed by cell-free, bacteria-free (filtered) extracts Chickens can be immunized against tumor transplantation and “filterable” tumor producing agent 1949, cell culture methods developed for viral passaging Viral Pathogenesis: the classical era 1950-1975 Three technological advances Culture of primary and continuous cell lines Detection of viral replication by cytopathic effects Titration of viruses by the plaque method Cell Lines HFB NIH 3T3 HeLa 0 hr. 5 hr. Cytopathic Effects Poliovirus (rounding and detachment) 8 hr. 24 hr. post-infection Murine Leukemia Virus (Syncytium formation) --multinucleated “giant” cell formation Titration of viruses by the plaque method --serial dilution of infectious innoculum onto monolayer of cells, --overlay with semi-solid medium (e.g. agarose) to limit viral spreading to only neighboring cells Viral Pathogenesis: the classical era 1950-1975 Three technological advances Culture of primary and continuous cell lines Detection of viral replication by cytopathic effects Titration of viruses by the plaque method Immunofluorescence Identification of viral antigens in infected cells or tissues Viral Pathogenesis: the classical era 1950-1975 Three technological advances Culture of primary and continuous cell lines Immunofluorescence Detection of viral replication by cytopathic effects Titration of viruses by the plaque method Identification of viral antigens in infected cells or tissues Measurement of immune responses to viruses Measurement of Antiviral antibodies neutralization End-point dilution assays complement fixation Hemagglutination Immunoprecipitation/immunoblotting Hemagglutination + - Viral Pathogenesis: the modern era 1975-present Molecular Biology Cloning of Viral Genomes Reverse Genetics Viral Pathogenesis in the 21st Century Emerging Viruses Ebola HTLV-1/HTLV-2 HIV-1, HIV-2 Hepatitis C Virus Borna Disease Virus Guantanto Virus Venezualan Haemorrhagic Fever Hanta Virus (Sin Nombre) Sabia Virus 1977 1980,1982 1983,1986 1989 1990 1991 1993 1994 Brazilian Haemorrhagic Fever Nipah Virus (Smallpox?!) 1999 ???? Diversity of Viruses How did viruses evolve? Why? Transposable elements; consequence of rapid gene evolution? Themes of Viral Pathogenesis “Nothing in biology makes sense except in the light of evolution” ---Theodore Dobzhansky Pathogenic consequences of most viral infections are due to the particular ways viruses have evolved to solve three major problems: Reproduction: RNA vs DNA viruses Spread: Limits of pathogenicity Evasion: viral-host co-evolution Pathology can be caused by host’s response to the viral infection (“collateral damage”) rather than to the direct virus infection itself Mutualistic adaptation; co-evolution of viral virulence and host resistance; achieve “balance” with natural host Biological control of wild rabbits: co-evolution of viral virulence and host resistance 1859, 12 European rabbits were introduced into an Australia farm; by 1928 more than a billion rabbits (>500/sq.mile) were ruining agriculture 1950, rabbit myxoma virus (>99% mortality rate) was introduced; by 1953, >95% of rabbit population was eliminated, by 1955, rabbit population began to increase. Reasons: Virulence of rabbit myxoma virus decreased; surviving rabbits developed increased resistance; changes in vector activity (mosquitoes) decreased efficiency of transmission Viral Pathogenesis in the 21st Century Molecular Understanding Required for Vaccine development Virocides Immunotherapy Biodefense/National Security