Science Spotlight

Go with the gut

From Dr. Meera Shenoy, in the Koch lab, Basic Sciences Division

Patients infected with the human immunodeficiency virus (HIV) frequently get bacterial pneumonia, which often leads to a fatal outcome. However, the biological factors that determine disease severity and outcome in HIV-infected patients remain unknown. The focus of previous studies has been on the microbiota of the lower airway, which are markedly dominated by several bacterial strains. Nevertheless, there has not been a clear association between airway microbiota and systemic immunity. Although HIV infection is known to perturb the gut microbiota, it is not known if the perturbation is related to HIV co-morbidities or to disease severity as defined by CD4 cell counts. CD4 T cells are white blood cells that play an important role in the immune system; a person’s CD4 cell count gives an indication of the health of the immune system. HIV damages the immune system because the virus targets CD4 T cells, thus low CD4 cell count in HIV-infected patients are indicative of high disease burden.   

Emerging evidence in both animal and human studies suggest that the gut microbiome and its metabolic products can play a key role in influencing immune function at remote mucosal sites, including airway responses to pathogenic infection. So, can the gut microbiome in HIV-infected pneumonia patients influence the behavior of immune cell populations such as CD4 cells, which are critical to controlling disease burden?

Dr. Meera Shenoy, currently a postdoc in the Koch lab in the Basic Sciences division, was intrigued by this problem when she was a graduate student with Dr. Susan Lunch at UCSF. “I’ve always been interested in host-microbial interactions, so for my graduate studies I was excited to delve into microbial ecology and try to understand what happens when the microbiota are no longer under the rigorous selection pressures of a healthy immune system” said Dr. Shenoy. She performed this work as a graduate student, and published it in a recent issue of Microbiome. She hypothesized that the composition of the gut microbiota of HIV-infected pneumonia patients is related to peripheral CD4 cell counts, and that the products of the gut microbiome influenced the behavior of immune cell populations necessary for the control of microbial infection.

 

Patients with low CD4 counts are enriched for shared airway microbes within the gut and depleted of healthy gut-associated microbes. Mean differences in reads/sample are plotted for the top differentiating taxa (genus-level identity provided). Significance was set at a false discovery rate q < 0.05, read difference ≥ 100 reads, and presence in ≥ 50% of the enriched group Figure from Dr. Shenoy

To address the hypothesis, the authors collected paired lower airway and stool samples from 153 HIV-infected patients with pneumonia from Uganda.  Bacterial microbiota profiles were generated using 16S rRNA amplicon sequencing.  This technique is based on the amplification of small fragments of one or two hyper-variable regions of the 16S rRNA gene, a common housekeeping genetic marker used to study bacterial phylogeny and taxonomy. The sequences of these fragments are then compared with reference sequences in curated databases for taxonomic identification. Interestingly, despite severe CD4 suppression in these HIV-infected patients, the authors found that their study population retained site-specific microbiota in the lower airways and gastrointestinal tract.

While composition of lower airway bacterial communities was not associated with CD4 status, gut microbiota diversity correlated with CD4 counts. The gut microbiota of HIV-infected patients with pneumonia who have progressed to acquired immune deficiency syndrome (AIDS), which develops as a result of advanced HIV infection destroying the immune system, and have extremely low CD4 counts (< 35 cells/ul) was compared to that of HIV-infected, non-AIDS patients with high CD4 counts (>295 cells/ul). The most severely ill patients as assessed by CD4 count shared strain level microbial taxa between their intestines and airways and were depleted of gut microbial genera typically associated with good health. The authors also found that gut microbial products modulated a pro-inflammatory macrophage effector phenotype based on patient CD4 cell count.

Dr. Shenoy explains the importance of this study: “Microbial communities at different sites of the body display niche specificity and pathogen exclusion during health. However, in the context of disease, increased sharing of microbes may take place between distinct anatomic sites due to epithelial barrier breakdown, loss of immune protection, and loss of appropriate metabolic signaling. Being able to study these interactions in humans, as opposed to animal models, is key because the stresses of changing environments, diet, and pathogen challenge constantly test the delicate equilibrium between the host and its microbial communities.”

This work also involved extensive collaboration between clinical care givers, research coordinators, and laboratory researchers on opposite sides of the world. “Being able to work with such a diverse group kept me grounded in the global health importance of my research goals and the challenges of keeping my basic science practical to the medical community” said Dr. Shenoy. Not only did she gain valuable insights from this work, it has also influenced her current interests in the Koch lab: “For my postdoc, I’m excited to continue learning about host-microbiota interactions, but instead of focusing on what happens during a state of disease, I’m now eager to investigate how healthy host-microbiota relationships are established in the neonate” said Dr. Shenoy.

Shenoy MK, Fadrosh DW, Lin DL, Worodria W, Byanyima P, Musisi E, Kaswabuli S, Zawedde J, Sanyu I, Chang E, Fong S, McCauley K, Davis JL, Huang L, Lynch SV. 2019. Gut microbiota in HIV-pneumonia patients is related to peripheral CD4 counts, lung microbiota, and in vitro macrophage dysfunction. Microbiome, 7(1), 37

This work was supported by the National Institutes of Health.

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