A Shifted Composition of the Lung Microbiota Conditions the Antifungal Response of Immunodeficient Mice

Abstract

The microbiome, i.e., the communities of microbes that inhabit the surfaces exposed to the external environment, participates in the regulation of host physiology, including the immune response against pathogens. At the same time, the immune response shapes the microbiome to regulate its composition and function. How the crosstalk between the immune system and the microbiome regulates the response to fungal infection has remained relatively unexplored. We have previously shown that strict anaerobes protect from infection with the opportunistic fungus Aspergillus fumigatus by counteracting the expansion of pathogenic Proteobacteria. By resorting to immunodeficient mouse strains, we found that the lung microbiota could compensate for the lack of B and T lymphocytes in Rag1–/– mice by skewing the composition towards an increased abundance of protective anaerobes such as Clostridia and Bacteroidota. Conversely, NSG mice, with major defects in both the innate and adaptive immune response, showed an increased susceptibility to infection associated with a low abundance of strict anaerobes and the expansion of Proteobacteria. Further exploration in a murine model of chronic granulomatous disease, a primary form of immunodeficiency characterized by defective phagocyte NADPH oxidase, confirms the association of lung unbalance between anaerobes and Proteobacteria and the susceptibility to aspergillosis. Consistent changes in the lung levels of short-chain fatty acids between the different strains support the conclusion that the immune system and the microbiota are functionally intertwined during Aspergillus infection and determine the outcome of the infection.

Childhood lower respiratory tract infections linked to residential airborne bacterial and fungal microbiota

“…However, the mechanisms behind their protective ability as well as how they integrate with the immune system during the response to infection is yet to be investigated. In this study, all the LRTI-related fungal genera belonged to the Ascomycota, a large fungal phylum with high abundance and diversity in most indoor and outdoor environments (Adams et al, 2021;Nunzi et al, 2021). The genus Aspergillus is known to be the most common of the Ascomycota and can be harmful to humans (Seyedmousavi et al, 2015).…”

“…Another interesting finding of this study is the potential protective effect of the phylum Bacteroidota against LRTI in under-five children which was consistent by DESEq2 and MaAsLin2. A murine model of aspergillosis stated that an increased risk of fungal pneumonia was associated with loss of protective anaerobes such as Clostridiales and Bacteroidota (Nunzi et al, 2021). However, the mechanisms behind their protective ability as well as how they integrate with the immune system during the response to infection is yet to be investigated.…”

Inborn errors of immunity and related microbiome

“…By investigating immunodeficient Rag1-/mice, Nunzi et al reported that lung microbiota was able to substitute the lack of B and T-cells by increasing the abundance of beneficial anaerobes such as Bacteroidota and Clostridia. In contrast, NSG (NOD scid gamma) mice, which have severe defects in the innate and adaptive immune responses, exhibited increased susceptibility to infections and were associated with reduced abundance of strict anaerobes and expansion of Proteobacteria (115). The characteristics of the main IEI associated with dysbiosis are summarized in Table 1.…”