Giving your neighbor the gift of virus susceptibility

SiphoviridaeVirus infections initiate when virions bind to receptors on the cell surface. It is well known that cells can be made susceptible to infection by providing DNA encoding the virus receptor. For example, mice cannot be infected with poliovirus, but become susceptible if they are given the human poliovirus receptor gene. Now we have learned that providing the receptor protein is sufficient to make cells susceptible to infection (link to paper).

Bacteriophages determine the composition of microbial populations by killing some bacteria and sparing others. Bacteriophages are typically host specific, a property that is largely determined at the level of attachment to host cell receptors. How resistant and sensitive bacteria in mixed communities respond to phage infection has not been well studied.

Several phages (including SPP1, pictured) of the soil bacterium Bacillus subtilis first attach to poly-glycosylated teichoic acids (gTA), and then to the membrane protein YueB, leading to injection of DNA into the cell. Cells that lack the gene encoding either of these proteins are resistant to infection.

When a mixed culture of resistant and susceptible B. subtilis cells were infected with phage SPP1, both types of cells became infected and killed. Infection of resistant cells depended on the presence of susceptible cells, because no infection occurred in pure cultures of resistant cells.

Both infected and uninfected bacteria release small membrane vesicles that contain proteins, nucleic acids, and other molecules. Phage SPP1 can attach to  membrane vesicles released by susceptible strains of B. subtilis, showing that they contain viral receptor proteins. Furthermore, phage SPP1 can infect resistant cells that have been incubated with membrane vesicles from a susceptible strain – in the absence of intact susceptible cells.

These results show that membrane vesicles released by susceptible bacteria contain viral receptors that can be inserted into the membrane of a resistant cell, allowing infection. Because phage infection can lead to transfer of host DNA from one cell to another, the results have implications for the movement of genes for antibiotic resistance or virulence. It’s possible that such genes may move into bacteria that have only ‘temporarily’ received virus receptors via membrane vesicle transfer.

These findings should also be considered when designing phage therapy for infectious diseases. The idea is to utilize phages that are host specific and can only destroy the disease-producing bacteria. It’s possible that the host range of such phages could be expanded by receptor protein transfer. As a consequence, unwanted genes might make their way into ‘resistant’ bacteria.

I wonder if membrane vesicle mediated transfer of receptors also occurs in eukaryotic cells. They shed membrane vesicles called exosomes, which contain protein and RNA that are delivered to other cells. If exosomes bear receptors for viruses, they might be able to deliver the receptors to cells that would not normally be infected. The types of cells infected by a virus would thereby be expanded, potentially affecting the outcome of viral disease.

Influenza A/Mexico/2009 (H1N1): Questions and answers

Here are my answers to questions about the currently circulating influenza H1N1 strain (formerly swine flu) sent by readers of virology blog.

Q: I am concerned about any changes the current AH1N1 virus may undergo as we enter the flu season in the Southern Hemisphere, and when it gets to Indonesia and faces H5N1. What are your expectations, if any of these situations?

I am not concerned about the current A/H1N1 strain recombining with avian H5N1 viruses. The reason is that the incidence of H5N1 viruses
in Asian pigs is low, suggesting that these viruses are not well adapted to pigs. I expect that the H1N1 viruses will undergo antigenic drift as they spread throughout the southern hemisphere, but I don’t anticipate that this will have a major impact on disease this season. There is no reason to believe that the viruses will evolve to a more virulent form.

Q: Has ever been shown sexual dimorphism in influenza? It turns out that 12 are women of 16 deaths blamed to the new influenza virus isolated in Mexico… this is too strange and together with the apparent absence of virulent markers in this new virus points to the presence of confounding factors in Mexico that explain deaths and should reduce the world-wide panic.

A: No, there has never been shown preference for infection, although males are slightly more susceptible to viral infections overall than women. But the difference is slight, and the numbers you cite are too small to draw any conclusions.

Q: Knowing that the Mexico/2009 Influenza A (H1N1) is part of a type of viruses that are unusual in that they copy RNA to DNA in the nucleus of a protein, where one of the segments acts as fusion (HA), and another (NA) aids in transportation to other proteins, isn’t it possible  that this specific one (the Mexico/2009 ) may teach us that there are heretofore unrecognized  innovative strategies in transcription, translation and replication of Influenza viruses?

A: I’m afraid you are misunderstanding the influenza virus replication strategy. The viral RNA is not copied into DNA in cells; the RNA is copied only into RNA. We copy the RNA into DNA to sequence the viral genome. If there were differences in the sequences of the Mexican strains from others we might learn something about viral pathogenicity, but I have not seen such differences so far.

Q: What is the most important protein, which I can use for the preparation  a vaccine against swine influenza?

A: If you had to pick only one viral protein, it would be the HA. This would be a so-called subunit vaccine; they have not been proven yet to be any better than inactivated whole virus vaccine.

Q: If face masks are useless, then why do surgeons wear them when they perform surgery? Sure, nobody with any common sense believes they offer 100% protection, but even a little extra protection is better than none. Another thing that I find outstanding is that nobody seems to be mentioning the use of protective gloves.

A: Face masks are not useless, just not terribly effective because they are not used properly. Surgeons use face masks because they work over exposed tissues and organs, and would otherwise breathe bacteria into the surgical incision. Gloves would become rapidly contaminated; they are useful in certain situations, for example while working in the field in trying to prevent contamination, preventing chemical contamination of the hands, and while working in a cell culture hood so that the cultures are not contaminated by organisms on the skin.

Q: I am a photographer and journalist based in Mexico City, and have been reporting on this outbreak for the last week. I know very little about virology, but have been learning what I can. I started a blog up as a vehicle for some of my observations on the disease and it’s cultural consequences which you can see here: So I had a couple questions about this situation, that my be stupid, but any answers you have would be very helpful.

Could this Influenza have originated in these feed lots. (The conditions are horrendous as can be expected in an America run feed lot, without American regulations).

A: This strain of influenza could have originated in any pigs raised for food, as long as humans are working with the pigs.

Q: How could the disease have been transmitted to humans? (The farmers thinks the thick swarms of flies on the sewage lots brought it).

A: The workers have rather close contact with the pigs. They could get it by touching the snout/mouth/respiratory secretions, or alternatively from aersols generated when the pigs breathe. These aerosols contain virus if the pig is infected.

Q: How could it have reached a child in a village with no direct contact with the farms?

A: Someone who had contact with pigs would be infected, then transfer it to the child elsewhere.

Q: I also wonder if contamination could have created a weakened respiratory system that allowed the disease to be more deadly, a theory I can’t help but believe regarding Mexico city which is so profoundly polluted

A: Those who get more severe disease with the same virus that is benign in others, likely have a suboptimal immune response. This can be a consequence of a genetic defect, of concurrent infection with an immunosuppressive microorganism, or environmental factors such as pollution or chemical injury.

Q: Is this normal for flu viruses to mutate into new strains (seemingly) every couple of years? I know it gives conspiracy kooks something new to accuse “The New World Order” of concocting to cause panic. Anyone?

A: Influenza viruses mutate continuously; as a result, new strains arise each year which evade existing immunity and cause epidemics of influenza. Every 20-30 years (or longer) a completely different strain emerges to which there is no prior immunity, and the result is a pandemic. Such new strains emerge from animal hosts, such as birds and pigs.

Q: First, what is the link, if any, between lack of immunity to a virus and the virulence or morbidity of the resulting viral disease?  In other words, should we fear a pandemic because: (1) more people will come down sick than during a normal flu season due the unfamiliarity of the virus; or (2) a higher percentage of the people who get sick will die; or (3) both?

A: Pandemic simply means global epidemic; many people are infected. It does not imply any severity of disease. So more people get sick, and if the strain is no more virulent than yearly influenza, the mortality is 0.1%. If the virus is more virulent (as in 1918) then the mortality is higher, 2.5% for that pandemic.

Q: Second, with respect to airplane travel and travel generally, I think the press and the authorities have done a very poor job distinguishing between systemic risk and personal risk.  Indeed, politicians in particular are hopelessly conflicted on this subject, notwithstanding the vice president’s widely denounced burst of candor.  Is it the case that: (1) while international travel poses no systmetic risk of spreading the virus, which is already present in North and South America, Europe and Asia, (2) individuals nonetheless greatly increase their chances of catching viral disease by traveling on airplanes, staying in hotels, etc.?

A: Yes, as I have written before in this blog, an airplane is a wonderful place to get influenza. But so are schools, workplaces, subways, and so on. We saw how an individual infected with SARS, by staying in a Hong Kong hotel, infected many people who then went on to other cities and spread the infection. Common sense is required. Travel that is not necessary should probably be curtailed.

Q: Finally, I have seen little intelligent discussion of the vastly different countermeasures deployed by different governments.  While everyone scoffs at Egypt, for instance, for slaughtering hundreds of thousands of pigs, no one mentions the radically different responses of the U.S. and Hong Kong authorities.  Has Hong Kong simply got the science wrong when they decide to quarantine hundreds of hotel guests for 10 days?

A: They are probably overreacting to the bad publicity they received with the SARS incident. They should have let the guest go; why should they treat guests any differently from any other locale?

Reader comment: Besides inherent deficiencies in the Mexican health system and initial delays by patients and doctors for a correct diagnosis, there is another scaring possibility for the high death rate in Mexico from the swine flu virus. That possibility is related to the instructions given to the doctors by the Ministery of Health to refrain to treat people with antivirals (Tamiflu, Relenza), unless they already have pulmonary signs (so too late), or they have a chronic disease in addition to the swine flu. Such instruction might save middle aged people (those with chronic diseases) and causes many neumonia cases among the more healthy youngsters. That may parcially explain why not only the death rate is so high, but also the age structure of the affected population. We’ll see if we can solve this questions in the future, because they are full of political consequences.

Q: I understand that with this new, novel strain of virus most, if not all people will not have immunity from previous exposure to the established strains.  However, many (or maybe just some people) will either avoid infection, or become infected yet experience no remarkable symptoms, or maybe just exhibit very mild symptoms rather than get really seriously ill.  What is at work when a person actually is infected yet not really “sick”?  A good immune system that allows infection but contains it quickly? or something else at work? Or just luck at avoiding virus particles? Example – I am 36 years old, and have never been diagnosed, or as far as I know, contracted  influenza.  I have had many other common ailments (many bouts of strep and colds, chicken pox, mononucleosis) over my years, but seemingly not flu virus.  I have never been vaccinated against flu.  What could account for this? Luck?  I find it impossible I haven’t ever come in contact with flu virus.  Assuming I have had contact with flu virus, why no remarkable illness for me? Clearly other infections can occur in me.  Are some people “immune” to all types of flu or react to it differently than others who suffer the common symptoms?

A: Our understanding of susceptibility to viral infection is rudimentary. When populations of humans or other animals are infected, many different responses may occur. Some people may be highly resistant, others may become infected, and some may fall in between. Of those infected, some may show clinical symptoms while others do not. Susceptibility to infection and disease vary independently. Some determinants include the immune system – your system may simply be more robust than the next person’s. There are genetic determinants of susceptibility; specific genes that regulate whether you can be infected or not. Age of the host, nutritional status, gender, cigarette smoking, mental status, and air pollution are some of the known factors.