Microbiology 445Medical VirologyJason Smith [email protected] Replication, Spread, PathogenesisReview Session for Exam 1: Friday, April 64:30-5:30 PMHSB T625Email one of us, if you would like to meet individually at other times.Virus Replication and SpreadSpread within populations and transmission between hostsEntry into and spread within hostReplication within host cellsVirus TransmissionIndirect TransmissionHumanHumanVectorVectorAnimalAnimalHumanVectorVectorAnthro-ponoses(humans are the only host)Direct TransmissionHumanHumanZoonoses(disease acquired from animals)AnimalAnimalHuman• Saliva/Mucus Influenza• Fecal matter Poliovirus• Blood HIV• Semen/Genital Secretions HIV/Zika• Urine Hantavirus• Mucosal surfaces Herpes Simplex• Skin HPV• Fomites: inanimate objects that can spread virus by touch (door knobs, etc.)Direct Transmission - HorizontalDirect Transmission - VerticalVirus must cross placenta to infect fetusVirus in birth canal or in bloodVirus present in milk• Humans can be infected with certain viruses from animals• “Human viruses” are most likely the result of a past zoonosis and adaptation of the virus to human as the only host• Many of the most severe viral diseases (rabies, Ebola, etc.) are zoonotic• Transmission from animals to humans can be direct or indirect• Zoonotic diseases are much more difficult to eradicateTransmission - Zoonoses• Vectors are living organisms that can transmit infectious diseases between humans or from animals to humans• Mosquitoes are common vectors, since they take blood from the host• Ticks can also be vectors for viruses• Other bloodsucking animals can be vectors for bacteria and parasitesIndirect Transmission - VectorsCulex Aedes aegypti Aedes albopictus• In some cases, there is an intermediate “amplifying” host between the natural reservoir and humansVenezuelan equine encephalitis virus: • Humans can be a “dead end host” if they do not subsequently transmit the virus – either directly or indirectlyTransmission – Amplifying HostGo et al., 2014• R0(“R naught”) is the basic reproduction number• The number of people each infected person will infect in a completely susceptible population• A product of:• Transmissibility – likelihood of infection if there is contact• Average rate of contact between susceptible and infected• Duration of infectiousness• R0>1 values mean spread through a population• R0<1 values mean the virus will die outTransmission – R0Disease R0Measles 12-18Smallpox 5-7HIV 2-5Mumps 2-5Ebola(2014outbreak)1.5-2.5• Enveloped viruses • Generally more fragile• Do not live very long outside of a host cell• Inactivated by heat, drying, detergents, pH• Non-enveloped viruses• Generally more stable• For which do you think fomite spreadis more common?• Which one is more likely to survive the gastrointestinal tract?Transmission – Virus PropertiesVirus Replication and SpreadSpread within populations and transmission between hostsEntry into and spread within hostReplication within host cells• 1. Eyes• 2. Mouth• Respiratory tract• Alimentary canal• 3. Skin• 4. Urogenital tract• 5. AnusPortals of EntryThese are also routes of viral shedding, but some viruses enter through one route and are shed by another• Mammalian skin is a highly effective barrier against viruses• The outer layer (epidermis) consists of dead cells – why does this limit virus infection?• Viruses that use this route generally require exposure of subcutaneous surfaces or abrasions • Herpes simplex infects in the lip area (or herpes gladitorium in abrasions)• Papilloma virus at joints like knuckles (warts)• Viruses also bypass the skin via bites (usually arthropods), needles, tattoos, surgery, other traumaPortals of Entry - Skin• Eye Adenovirus (conjuctivitis)• Nose and mouth Herpes simplex (HSV)• Genital tract Sexually transmitted viruses:HSV, HIV, HPV• Respiratory tract – Most common route• Alimentary canal – fecal/oral transmission• Why are mucosal layers a preferred site?• Single layer epithelium with no dead layer• Viruses live longer in damp environmentsPortals of Entry –Mucous Membranes• Virus infects initial susceptible cell• Must overcome host defenses (immunity) and environment• Dictated by tropism – the capacity of a virus to infect specific cells, tissues, or species• Localized spread of virus occurs by cell to cell spread or limited diffusion• Some virus infections remain localized to site of entry (common cold viruses, HPV)Spread – Primary Infection• After amplification at the primary site of infection, some viruses spread within the body• Route 1: Bloodstream and lymphatics• Viremia – virus in the blood• Via infection of lymphocytes (cell associated)• Cell-free in blood or lymph• Route 2: Nervous system• Virus can infect the brain from the blood by crossing the blood-brain barrier• Infect peripheral nerves and travel within nerves and sometimes to the central nervous system (CNS)Spread – SystemicSpread – Poliovirus Example• Initial infection of cells and localized spread• Intestinal epithelial cells for poliovirus• Spreads to lymph node and multiplies• Primary viremia• Fever, malaise, non-specific symptoms • Infection of secondary sites• Brown fat and muscle for polio• More amplification• Secondary viremia• Infection of other organs• CNS for poliovirus• Secretion• Viruses that cause rashes follow a similar paradigmSpread – Rabies Virus ExampleWhere does disease occur?• Primary site of infection• Lungs common cold viruses• Intestines norovirus, rotavirus• Mucous membranes Herpes simplex• Skin Papillomavirus• Eye Adenovirus, herpesviruses• Secondary site of spread• Liver Hepatitis viruses• Brain and CNS Rabies, herpes simplex• Blood HIV• Disseminated disease• Skin (rash) Small pox, measlesVirus Replication and SpreadSpread within populations and transmission between hostsEntry into and spread within hostReplication within host cellsSteps of Viral Replication1. Attachment2. Penetration3. Uncoating of nucleic acid4. Viral protein expression4a: Early viral protein synthesis5. Replication of viral genome4b: Late viral protein synthesis: structural proteins6. Assembly7. Release8. Maturation (can occur before release)Replication of Naked VirusesAttachmentMaturationPolymeraseEarly protein expressionNon-structural