New research from the University of North Carolina School of Medicine suggests that the microbiome may not always protect against human pathogens.
Using a microbiome-free (germ-free) precision animal model for the first time, researchers demonstrate that the microbiome significantly influences Epstein-Barr virus acquisition and HIV infection and plays a role in the disease process.
“These findings provide the first direct evidence that the resident microbiota can have a significant impact on the establishment and pathology of infection with two distinct human-specific pathogens,” said Angela Wahl, one of the leaders of the study. ) explained that she has published it in the scientific journal “Nature Biotechnology”.
Over the past decade, the gut microbiome has attracted enormous interest from scientists and non-scientists alike. Recent research has shown that the bacteria and other microbes in our gut play a supportive role in immunity, metabolism, digestion, and fighting “bad bacteria” that try to invade our bodies.
To make this new discovery, the researchers needed to create a “humanized” mouse model that mimics the human immune system. Once exposed to the virus, the humanized model can replicate the virus like a human and can be used in research.
But the researchers needed to go further. They needed to compare traditional humanized mouse models with those without the microbiome (germ-free). That meant they needed to create a sterile, humanized mouse model, the first of its kind.
So they had to find a way to humanize animals without being exposed to any bacteria, including those that live in food, skin, air, or anywhere else in the external environment. To do this, they used a custom-built surgical isolation room, which is basically a “big sterile bubble” complete with a specialized glove box and microscope.
HIV is mainly transmitted through the gastrointestinal tract. For example, rectal exposure in men who have sex with other men accounts for more than half of new HIV infections. Breastfeeding is an example of oral exposure that can also transmit HIV to the baby.
In the study, animals colonized with a resident microbiome had a 200 percent higher rate of rectal HIV infection than germ-free animals. Likewise, animals colonized with a resident microbiota had a 300% higher rate of oral HIV infection compared with germ-free animals.
The researchers also found that animals colonized with the resident microbiota had 34-fold higher levels of HIV RNA in plasma and more than 1,000-fold higher levels of HIV RNA in tissues compared to germ-free mice.
The researchers then compared colonized and germ-free animals and showed that the presence of the resident microbiota increased the frequency of CCR5+CD4+ T cells, which are the main target of whole-gut HIV infection.
The results suggest that the increase in HIV acquisition and replication is at least in part due to a higher density of locally infected target cells following oral or rectal HIV exposure.
“This is a very important finding. Each individual has a unique composition of microbes in their gut. In the future, it will be important to assess how this diversity among people affects their risk of HIV infection and subsequent disease course,” Val said.
Epstein-Barr’s findings are also important. Epstein-Barr is a DNA herpes virus that infects B cells and causes mononucleosis. Nearly 95% of adults have an underlying Epstein-Barr infection, but in some people with compromised immune systems, the infection may affect the development of certain types of cancer, such as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, Burkitt lymphoma and nasopharyngeal carcinoma.
The researchers also found that mice with normal microbiomes exposed to Epstein-Barr developed large macroscopic tumors in multiple organs, including the spleen, liver, kidney, and stomach. These tumors were virtually absent in Epstein-Barr-infected germ-free mice.
Regardless, future studies will be necessary to assess possible mechanisms of enhanced Epstein-Barr infection and tumorigenesis in the presence of a resident microbiota.
The researchers will now try to determine the factors that determine whether the microbiome is involved in the persistence of HIV and Epstein-Barr infection throughout the body and whether the microbiome also affects other specific human pathogens.
More specifically, they wanted to understand how the microbiome contributes to HIV and Epstein-Barr infection. They also want to determine which specific microbial strains contribute to the virus’ ability to replicate and cause disease, and most importantly, which microbial strains protect the host from the virus. They were particularly interested in whether there were other latent viruses that were influenced by the microbiome.
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