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Transcript
Viral virulence Lecture 15 Biology W3310/4310 Virology Spring 2015 Serious illness doesn’t bother me for long because I am too inhospitable a host. —ALBERT SCHWEITZER Animal models • • Human viruses in animals Animal viruses that resemble human infecNon Principles of Virology, ASM Press PVR PVR-‐Tg Viral virulence • • • Capacity of a virus to cause disease in a host Virulent vs avirulent or aQenuated virus Virulence can be quanNtated: -‐ Mean Nme to death -‐ Mean Nme to appearance of symptoms -‐ Measurement of fever, weight loss -‐ Measurement of pathological lesions (poliovirus); reducNon in blood CD4+ lymphocytes (HIV-‐1) Viral virulence Principles of Virology, ASM Press Viral virulence is a rela1ve property • Influenced by dose, route of infecNon, species, age, gender, and suscepNbility of host • • Cannot compare virulence of different viruses For similar viruses, assays must be the same Virulence depends on route of inocula1on Lymphocy:c choriomeningi:s virus Dose Route Outcome 100,000 PFU Intraoperitoneal Survival 1 PFU Intracranial Death Principles of Virology, ASM Press Go to: m.socraNve.com room number: virus Which statement about viral virulence is wrong? 1. It can be influenced by dose, route of infecNon, species, age, gender, and suscepNbility of host 2. It can be quanNtated by measurement of fever 3. Ebola virus is more virulent than human papillomavirus 4. It is the capacity of a virus to cause disease in a host 5. When comparing virulence, the assays must be the same 1 Viral virulence • Major goal of virology is to idenNfy viral and host genes that determine virulence • Virulence genes usually idenNfied by mutaNon: a virus that causes reduced or no disease in a specified system Iden1fying virulence genes Principles of Virology, ASM Press Viral virulence genes • • • • • • Viral replicaNon Invasiveness Tropism Modify the host defense mechanisms Enable the virus to spread in the host Intrinsic cell killing effects Virulence determinants may not encode proteins A=enuated Sabin vaccine strains of poliovirus contain a muta:on in the 5’-‐noncoding region that reduces neurovirulence Principles of Virology, ASM Press Poliovirus replica1on in mouse brain Principles of Virology, ASM Press Gene products that modify host defense • Immune modulators -‐ -‐ -‐ -‐ • Apoptosis, autophagy, proteins (Apobec3G) Virokines and viroceptors Complement binding proteins Modifiers of MHC I, II pathways Ocen not required for growth in cell culture Viral virulence genes Gammaherpesvirus 68 M3 gene encodes a chemokine receptor Principles of Virology, ASM Press Toxic viral proteins NSP4 nonstructural glycoprotein of rotaviruses: viral enterotoxin Regula1on of virulence by a cellular protein: TRIM5α • • • Old world monkeys are not infected by HIV-‐1 Virions enter but encounter a block before RT RestricNon mediated by species-‐specific protein TRIM5α that acts on the viral capsid miRNAs • miR-‐122, liver-‐specific miRNA required for HCV replicaNon • AnN-‐miR-‐122 reduces HCV yield in chimpanzees J. Cell Biol. Vol. 199 No. 3 407–412 Mechanisms of cell injury by viruses • CytolyNc viruses: cytopathic effects (apoptosis, necrosis, pyroptosis) • Viroporins • Viral inhibiNon of host protein and RNA synthesis, leads to loss of membrane integrity, leakage of enzymes from lysosomes, cytoplasmic degradaNon • SyncyNum formaNon by enveloped viruses (parainfluenza, HIV) Role of the microbiome in viral replica1on Poliovirus infec:on of TgPvr mice Should we make viruses more virulent? + IL-‐4 gene Mice • Highly lethal in geneNcally resistant mice (strong cell response) • Suppressed memory response The obsession with viral virulence • • Limited sequences available from outbreak • Unknown if this strain is sNll in circulaNon 2014 isolate has HA D225N change ‘associated with serious illness’ Go to: m.socraNve.com room number: virus Which statement about determinants of viral virulence is incorrect: 1. 2. 3. 4. 5. Virulence genes can encode viral proteins Virulence genes can encode cellular proteins They are the same in all viruses They can be found in untranslated regions They may encode immune modulators 2 Immunosuppression • Global reducNon of the immune response caused by virus infecNon • Mechanisms -‐ -‐ ReplicaNon in one or more cells of immune system -‐ Viral proteins acNng as viroceptors or virokines (immune modulators) PerturbaNon of cytokine homeostasis and intracellular signaling Immunosuppression during measles infec1on Measles virus immunosuppression • DendriNc cells and monocytes are infected, anNgen-‐ presenNng acNvity compromised • • CirculaNng T lymphocytes are decreased by 50% Aberrant cytokine responses: IL-‐4 and IL-‐10 increased, skews Th1 to Th2 and reducing macrophage acNvaNon Examples of immunosuppression Virus Disease Cells infected Manifestation Measles Measles Monocytes, DC Thymic epithelial cells Reduced T cells Enhanced infections Rubella Rubella Lymphoid cells Persistent rubella infection HIV AIDS CD4+ T cells monocytes Opportunistic infections Neoplasia Host genes that control host suscep1bility to viral disease • flv gene of mice determines suscepNbility to flavivirus • flv encodes 2’-‐5’-‐oligo(A) synthetase Human determinants of suscep1bility • • • • Ccr5-‐delta32 mutaNon protects vs HIV-‐1 infecNon Present in 4-‐16% of European descent Stem cell therapy cured German AIDS paNent HIV gets the zinc finger: hQp://www.virology.ws/ 2014/03/19/hiv-‐gets-‐the-‐zinc-‐finger/ Principles of Virology, ASM Press Herpes simplex encephali1s • Rare and potenNally fatal CNS infecNon, ~1 case/ 250,000/yr • • 70% mortality if untreated Two peaks of incidence: 6 mo -‐ 3 yr (primary infecNon) and >50 yr (reacNvaNon from latency) Principles of Virology, ASM Press Human determinants of suscep1bility • • GWAS, SNPs MutaNons in TLR3, UNC-‐93B, TRIF or TRAF3 predispose human carriers to HSV encephaliNs Influenza severity and IFITM3 • • IFITM3 is an ISG encoding a transmembrane protein • Humans hospitalized with severe influenza are enriched for a mutaNon in IFITM3 gene EssenNal for controlling influenza morbidity and mortality in mice IFITMs also inhibit dengue, HCV, Ebola Virus suscep1bility mapping to MHC Virus suscep1bility mapping to MHC Elite controllers • Long-‐term nonprogressors: low HIV loads without anNretrovirals • • MulNple traits responsible Associated with specific MHC I alleles (HLA-‐B57) Principles of Virology, ASM Press Viral co-‐infec1ons: HIV-‐1 and HSV-‐2 • • HSV-‐2 enhances HIV infecNon of Langerhans cells • • AMP LL-‐37 enhances HIV-‐1 infecNon of LCs HSV-‐2 sNmulates producNon of anNmicrobial pepNdes by epithelial cells LL-‐37 up-‐regulates HIV-‐1 receptors CD4 and CCR5 HSV-‐2 HIV-‐1 CD4, CCR5 LL-‐37 Principles of Virology, ASM Press Go to: m.socraNve.com room number: virus Which of the following are examples of SNPs that control suscep1bility to viral disease? 1. Viral co-‐infecNons 2. Ccr5-‐delta32 3. MutaNons in tlr3 that predispose to herpes simplex encephaliNs 4. The flv gene 5. All of the above 4 Age • Very young and very old humans most suscepNble to disease • Young -‐ immaturity of immune response; greater freedom from immunopathology -‐ LCM i.c. adult mice lethal; infant mice survive (T cell response) • Old -‐ less elasNc alveoli, weaker respiratory muscles, diminished cough reflex Influenza, US, 1911-‐1915 Age excep1ons • Poliovirus, mumps virus, measles virus infecNons milder at young age; beQer balance of protecNve and pathogenic immune response at this age? • 1918 influenza pandemic lethal for very young, very old, and unexpectedly for young adults 18-‐30 yr old US 1911-‐1915 US 1918 Perhaps lacked protecNve immunity which would be conferred by previous infecNon with related virus Principles of Virology, ASM Press Other determinants • Males slightly more suscepNble to viral infecNons than females • Pregnancy: hepaNNs A, B, E, influenza more lethal, polio more common • MalnutriNon increases suscepNbility because physical barriers and immune response are compromised -‐ For this reason, measles is 300 Nmes more lethal in developing countries than Europe, N. America Other determinants • CigareQe smoking increases suscepNbility to respiratory infecNons • • Air polluNon increases respiratory disease Stress causes increased suscepNbility
