TWiV 460: Penn, a great sandbox for science

Vincent travels to the University of Pennsylvania and speaks with virologists Gary Cohen, Scott Hensley, Carolina Lopez, and Susan Weiss about their careers and their research.

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TWiV 457: The Red Queen meets the White Rabbit

Brianne returns to the TWiV Gang to discuss the distribution of proteins on the influenza viral genome, and the evolution of myxoma virus that was released in Australia to control the rabbit population.

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TWiV 452: Kiss that frog

Lynda Coughlan joins the weekly virtual bus companions for a discussion of a host defense peptide from frogs that destroys influenza virus, and mouse models for acute and chronic hepacivirus infection.

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Kermit’s urumi

Hydrophylax bahuvistaraFrogs don’t get flu (as far as I know) but their skin contains a peptide that inhibits the replication of influenza virus (link to paper).

Frog skin contains host defense peptides (HDPs), part of the innate immune defenses of many species. They were first found in amphibians by Michael Zasloff, who, as part of his research, performed surgery on frogs and then returned them to an aquarium – which was not sterile. He wondered why the frogs always healed without signs of infection, which lead him to discover the antimicrobial peptides, called magainins, in frog skin. HDPs had been first discovered years earlier in the silk moth.

Amphibian HDPs are active against bacteria, fungi, viruses, and protozoa. To discover HDPs that inhibit influenza virus, 32 HDPs from skin secretions of the Indian frog Hydrophylax bahuvistara were screened by mixing them with virus followed by a plaque assay. One peptide was found to potently inhibit influenza virus replication without cell toxicity. It was called urumin, after the whip sword known as urumi.

Urumin inhibits infectivity of influenza H1N1 viruses far better than H3N2 viruses. The reason is that the peptide targets the viral H1 hemagglutinin, one of two glycoproteins in the viral envelope. Furthermore, the peptide appears to interact with the conserved stalk region of the HA glycoprotein, and not with the globular head.

Currently two different antiviral drugs, oseltamivir and relenza, are used to control influenza virus infection. Viruses resistant to these drugs were still inhibited by urumin, indicating that should urumin ever be licensed, it would be useful in the event that oseltamivir and relenza resistant viruses became more common.

Examination of urumin treated virus particles by electron microscopy revealed that they are disrupted by the peptide. How urumin breaks influenza virus particles is not known. However, the HDP nisin destroys bacteria by first binding to a bacterial membrane component, then moving into the membrane. After binding to HA, urumin might in a simlar way disrupt the membrane of influenza virus particles.

Urumin also reduced disease, death, and the amount of virus in the lung in mice intranasally infected with influenza virus.

These observations suggest that urumin is worthy of additional study as an influenza virus inhibitor. HDPs are attractive antimicrobial compounds because resistance to their mechanisms of action is lower than for other types of inhibitors. However, enthusiasm for urumin is dampened because, despite extensive study, no HDP has yet been approved by the US Food and Drug Administration for use in humans. The obstacles to therapeutic success of HDPs have not been identified.

TWiV 446: Old sins die hard

The TWiV hosts review an analysis of gender parity trends at virology conferences, and the origin and unusual pathogenesis of the 1918 pandemic H1N1 influenza virus.

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TWiV 436: Virology above Cayuga’s waters

At Cornell University in Ithaca, New York, Vincent speaks with Susan, Colin, and Gary about the work of their laboratories on parvoviruses, influenza viruses, and coronaviruses that infect dogs, cats, horses and other mammals.

You can find TWiV #436 at microbe.tv/twiv, or listen below.

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TWiV 396: Influenza viruses with Peter Palese

TWiVVincent speaks with Peter Palese about his illustrious career in virology, from early work on neuraminidases to universal influenza virus vaccines, on episode #396 of the science show This Week in Virology.

You can find TWiV #396 at microbe.tv/twiv, or listen below.

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Influenza virus in breast milk

Ferret mother-infantDuring breastfeeding, mothers provide the infant with nutrients, beneficial bacteria, and immune protection. Fluids from the infant may also enter the mammary gland through retrograde flux of the nipple. Studies in a ferret model reveal that influenza virus replicates in the mammary gland, is shed in breast milk and transmitted to the infant. Virus may also travel in the opposite direction, from infant to mother.

The role of the mammary gland in influenza virus transmission was studied using a ferret model comprising lactating mothers and nursing infants. Intranasal inoculation of nursing mother ferrets with the 2009 H1N1 influenza virus lead to viral replication and development of influenza in both mother and infant. When the study design was reversed, and 4 week old nursing ferrets were inoculated intranasally with the same virus, viral replication and disease ensued first in the infants, and then in the mothers. Infectious virus was recovered both in the mammary glands and in the nipples at day 4 post infant inoculation, and in mother’s milk from 3-5 days post infant inoculation. Histopathological examination of sections of mammary glands from infected mothers revealed destruction of the mammary architecture.

These results show that nursing infants may pass influenza virus to mothers. It seems clear that influenza virus replicates in the mammary gland and that infectious virus is present in milk. How does this virus infect the mother? One possibility is that infection is transmitted by respiratory contact with virus-containing milk, or by inhalation of aerosols produced by nursing. How influenza virus in the mammary gland would reach the mother’s lung via the blood to cause respiratory disease is more difficult to envision and seems unlikely.

When influenza virus was inoculated into the mammary gland of lactating mothers via the lactiferous ducts, both mother and breast feeding infant developed serious influenza. Infectious virus was detected first in the nasal wash of infants, then later in the nasal wash of mothers. Breast milk contained infectious virus starting on day 2 after inoculation. Histopathological examination of sections from infected mammary glands revealed destruction of glandular architecture and cessation of milk production. This observation is consistent with the results of gene expression analysis of RNA from virus infected mammary glands, which revealed reduction in transcripts of genes associated with milk production.

To determine if human breast cells can be infected with influenza virus, three different human epithelial breast cell lines were infected with the 2009 H1N1 virus strain. Virus-induced cell killing was observed and infectious virus was produced.

Even if we assume that influenza virus can replicate in the human breast, the implications for influenza transmission and disease severity are not clear. Transmission of HIV-1 from mother to infant by breast milk has been well documented. In contrast to influenza virus, HIV-1 is present in the blood from where it spreads to the breast. Most human influenza virus strains do not enter the blood so it seems unlikely that virus would spread to the breast of a mother infected via the respiratory route. However, viral RNA has been detected in the blood of humans infected with the 2009 H1N1 strain, the virus used in these ferret studies. Therefore we cannot rule out the possibility that some strains of influenza virus spread from lung via the blood to the breast, allowing infection of a nursing infant. Some answers might be provided by determining if influenza virus can be detected in the breast milk of humans with influenza.

What would be the implication of a nursing infant infecting the mother’s breast with influenza virus? As I mentioned above, it seems unlikely that this virus would enter the blood, and even if it could, how would the virus infect the apical side of the respiratory epithelium? What does seem clear is that viral replication in the breast could lead to a decrease in milk production which could be detrimental to the infant. If the mother had multiple births, then influenza virus might be transmitted to siblings nursing on the infected mother.

Are you wondering how an infant drinking influenza virus-laded breast milk acquires a respiratory infection? Recently it has been shown that influenza virus replicates in the soft palate of ferrets. The soft palate has mucosal surfaces that face both the oral cavity and the nasopharynx. Ingested virus could first replicate in the soft palate, then spread to the nasopharynx and the lung. A simpler explanation is that nursing produces virus-containing aerosols which are inhaled by the infant.

TWiV 355: Baby’s first virome

On episode #355 of the science show This Week in Virology, the TWiV team considers the effect of a Leishmaniavirus on the efficacy of drug treatment, and the human fecal virome and microbiome in twins during early infancy.

You can find TWiV #355 at www.microbe.tv/twiv.

TWiV 351: The dengue code

On episode #351 of the science show This Week in Virology, the Masters of the ScienTWIVic Universe discuss a novel poxvirus isolate from an immunosuppressed patient, H1N1 and the gain-of-function debate, and attenuation of dengue virus by recoding the genome.

You can find TWiV #351 at www.microbe.tv/twiv.