Viral infections and the microbiota

By: Helen Beilinson

Take home points:

1)    The microbiota can influence viral infections—exacerbating disease or preventing disease—so we need to be mindful of how we take antibiotics during viral infection

2)    Antibiotic treatment during flu infection can exacerbate disease

3)    Antibiotic treatment during other viral infections could prevent viruses from taking advantage of immunosuppressive properties of microbiota

 The microbiota—two words that have been splattered across scientific papers, the evening news, and “yogurt for women” packages. The multitude of bacterium that live within and on us constitutes, essentially, another organ that plays a role in many aspects of development and maintenance of the larger organism. It has been long appreciated that the microbiota plays a beneficial role in a host’s metabolism. However, only recently it has been shown that the microbiota is a significant player in the host’s immune system. In fact, it has a huge influence on how we interact with external pathogens and on the pathogenesis (the development of disease) of these pathogens. The predominantly bacterial microbiota live mostly at mucosal surfaces of the host (such as the gastrointestinal tract, genital mucosa, and upper airways), as well as on the skin. Interestingly, viruses are predominantly spread through routes where they would interact with the aforementioned microbiota. Thus, it is highly probable that the microbiota and viral pathogens interact and influence each other in some way. In fact, it has been documented that the microbiota can either obstruct or advance infections of various viral pathogens (or have no effect).

In mouse studies, it has been shown that eliminating the microbiota, either through antibiotics treatment (treatments against bacteria) or by raising mice germ-free (meaning that they have never been colonized with any bacteria), is very detrimental during influenza infection. Mice have more viral particles, higher mortality rates, and more degeneration and death of their lung tissue without their proper bacterial population. The mechanism of microbiota-dependent protection currently is unknown. This trend is incredibly important to study for its implications in human health. Flu infection changes the landscape of our lungs, making it easier for bacteria to infect the lungs. One such bacterium is Streptococcus pneumoniae, a causative agent of pneumonia. The most fatal cases of influenza are due to such secondary bacterial infections. Increases in mortality due to co-infection have been confirmed in mouse models. When patients enter the hospital with bacterial pneumonia, they are placed on antibiotics. This could potentially exacerbate flu disease by eliminating the beneficial bacteria of the patient’s microbiota, leading to death. Unfortunately, there have not yet been studies to show that antibiotic treatment causes patients to fare worse in co-infection situations.

In theory, our immune systems are activated once they sense an invader via certain molecular patterns that are unique to the invaders. For all intents and purposes, however, the molecular patterns decorating pathogenic bacteria are the same as those decorating the bacteria composing our microbiota. Although one of the current mysteries of the microbiota is why our immune system doesn’t eliminate it, it is known that these commensal organisms possess immunosuppressive properties. For example, a molecule that decorates the surface of particular bacteria is called lipopolysaccharide (LPS). There are various forms of LPS, some forms are immunostimulatory, while others, such as those expressed by the microbiota, are immunosuppressive. It has been shown that there are viruses that take advantage of the immunosuppressive properties of commensal LPS to dampen the responses of the host, allowing for active viral replication. Thus, although depletion of a host’s microbiota may be detrimental in flu infection, in cases where the microbiota aids viral replication and disease progression, antibiotics may be a source of treatment.

Studies in mice utilizing two different retroviruses (the family of viruses to which HIV belongs) have shown that these viruses require the presence of the microbiota to be present to flourish. By binding to LPS of the gut bacteria, the viral particles stimulate immunosuppressive pathways, allowing the virus to replicate without the host attempting to eliminate it. These studies were done in mice with murine viruses, so the question remains: Do human viruses interact similarly with LPS? Potentially.

It has been shown that HIV virions can directly bind to LPS molecules. It has also been shown that the presence of LPS during HIV infection (in a series of experiments in cells, not full organisms) decreases the “activated” state of antiviral immune cells, called plasmacytoid dendritic cells, preventing them from potently attacking infected cells. LPS is recognized by Toll-like receptor 4 (TLR4) in our immune system. In an unknown fashion, different LPS variants stimulate TLR4 to produce either a pro- or anti-inflammatory state, which is defined by immune signaling molecules called cytokines. An HIV protein, Tat, has been shown to stimulate the same immunosuppressive pathway as the mouse viruses by interacting with TLR4. This study did not show whether or not LPS was present in the experiments shown (LPS is a pesky molecule that is incredibly difficult to eliminate in a lab setting). Either way, it points to interesting evidence that HIV, as the mouse retroviruses, has possibly evolved the ability to take advantage of the immunosuppressive properties of the microbiota to allow for its replication. Thus, antibiotic treatment could be a potential treatment for HIV replication by decreasing the amount of commensal-expressed LPS that the virus may take advantage of to evade the immune system.

Living predominantly in areas that are directly exposed to the elements and invading pathogens, our microbiota may hold essential information regarding how our body battles infection and either wins or loses. The modulation of our live-in bugs will certainly be a future step in medicine in aiding the treatment of various infections, including those of viral pathogens. So next time you have a viral infection, be sure to ask your doctor whether it is safe for you to take antibiotics—or whether it could possibly help your immune system eliminate the infection.

It is important to note that neither the flu nor the HIV findings have been confirmed in humans, particularly the HIV studies. The intricacies of the microbiota, and particularly the details of how it interacts with intruding viruses, are still very enigmatic. Presented here are very brief summaries of very few papers on this topic, these should not be taken as medical advice.