Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies

Doron, Itai; Leonardi, Irina; Li, Xin V.; Fiers, William D.; Semon, Alexa; Bialt-DeCelie, Meghan; Migaud, Mélanie; Gao, Iris H.; Lin, Woan-Yu; Kusakabe, Takato; Puel, Anne; Iliev, Iliyan D.

doi:10.1016/j.cell.2021.01.016

Cited by 134 publications

(131 citation statements)

References 78 publications

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“…S5 A and B). These findings suggest that Myo1f may regulate mouse B cell development that might further play a role in the observed antifungal immunity defects in Myo1f-KO mice as recently demonstrated by Itai Doron and colleagues that host protective antifungal antibodies play an indispensable role in the antifungal immunity (58). This point needs to be further investigated in the future.…”

Section: Discussionsupporting

confidence: 57%

“…S5 C and D). These findings suggest that Myo1f may regulate mouse B cell development that might further play a role in the observed antifungal immunity defects in Myo1f KO mice as recently demonstrated by Itai Doron and colleagues that gut commensal fungi-induced antibody repertoire plays an indispensable role in antifungal immunity (58). Myo1f-KO mice were more susceptible to C. albicans-induced fungal sepsis than WT control mice, which was shown by the higher mortality rate, faster weight loss, and higher fungal burden of Myo1f-deficient mice compared to control mice (Fig.…”

Section: Proteins (Datasets S4-s6supporting

confidence: 64%

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MYO1F regulates antifungal immunity by regulating acetylation of microtubules

Sun

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Opportunistic fungal infections have become one of the leading causes of death among immunocompromised patients, resulting in an estimated 1.5 million deaths each year worldwide. The molecular mechanisms that promote host defense against fungal infections remain elusive. Here, we find that Myosin IF (MYO1F), an unconventional myosin, promotes the expression of genes that are critical for antifungal innate immune signaling and proinflammatory responses. Mechanistically, MYO1F is required for dectin-induced α-tubulin acetylation, acting as an adaptor that recruits both the adaptor AP2A1 and α-tubulin N-acetyltransferase 1 to α-tubulin; in turn, these events control the membrane-to-cytoplasm trafficking of spleen tyrosine kinase and caspase recruitment domain-containing protein 9. Myo1f-deficient mice are more susceptible than their wild-type counterparts to the lethal sequelae of systemic infection with Candida albicans. Notably, administration of Sirt2 deacetylase inhibitors, namely AGK2, AK-1, or AK-7, significantly increases the dectin-induced expression of proinflammatory genes in mouse bone marrow–derived macrophages and microglia, thereby protecting mice from both systemic and central nervous system C. albicans infections. AGK2 also promotes proinflammatory gene expression in human peripheral blood mononuclear cells after Dectin stimulation. Taken together, our findings describe a key role for MYO1F in promoting antifungal immunity by regulating the acetylation of α-tubulin and microtubules, and our findings suggest that Sirt2 deacetylase inhibitors may be developed as potential drugs for the treatment of fungal infections.

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Section: Discussionsupporting

confidence: 57%

Section: Proteins (Datasets S4-s6supporting

confidence: 64%

MYO1F regulates antifungal immunity by regulating acetylation of microtubules

Sun

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…This occurs via innate immune mechanisms that, interestingly, also increase resistance against other fungal (A. fumigatus) and bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) infections [13]. Fungal gastrointestinal colonization (the mycobiota) has recently been shown to induce antifungal IgG responses, protecting mice against infection with C. albicans or Candida auris [14]. Therefore, the commensal C. albicans pool seems to play a role in generating protective immunity against C. albicans infections, but also other pathogens.…”

Section: Does C Albicans Gut Colonization Have Beneficial Effects For the Host?mentioning

confidence: 99%

Candida albicans colonization of the gastrointestinal tract: A double-edged sword

et al. 2021

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Candida albicans is not only a common commensal of the vaginal and gastrointestinal tract (GIT) of humans, but also an important cause of infections worldwide and is therefore considered an opportunistic pathogen. C. albicans can cause superficial but also more severe, frequently life-threatening, systemic infections. The latter may occur when the microbiota is disturbed and immune defenses are compromised, thus allowing the dissemination of the fungus from commensal pools, in particular the GIT, to vital organs. Therefore, gastrointestinal C. albicans colonization can be seen as a predisposing factor of life-threatening infections. However, recent evidence indicates that commensal coexistence of C. albicans with the human host is not only detrimental. In fact, beneficial effects of C. albicans colonization to human health, most likely, have been an evolutionary pressure for its establishment as a commensal. Here, we review recent studies that demonstrate both beneficial and detrimental effects of this pathobiont to human health upon colonization of the human gut.

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“…However, Candida albicans gut colonization also promoted susceptibility to T H 17 cell-mediated airway inflammation and correlated with systemic levels of T H 17 cell inflammation ( 62 ). In humans, the gut mycobiome induced antifungal antibody production that protects against systemic fungal infections in a caspase recruitment domain-containing protein 9 (CARD9) dependent way ( 63 ). Commensal fungi seem to have certain anti-inflammatory properties as a disturbance of the fungal gut community aggravated colitis in a mouse model ( 64 ).…”

Section: The Microbiome Of the Gastrointestinal Tract: Local Effects On Immunitymentioning

confidence: 99%

The Mammalian Metaorganism: A Holistic View on How Microbes of All Kingdoms and Niches Shape Local and Systemic Immunity

Runge

Rosshart

2021

Front. Immunol.

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The field of microbiome research has developed rapidly over the past decades and has become a topic of major interest to basic, preclinical, and clinical research, the pharmaceutical industry as well as the general public. The microbiome is a complex and diverse ecosystem and defined as the collection of all host-associated microorganisms and their genes. It is acquired through vertical transmission and environmental exposure and includes microbes of all kingdoms: bacteria, archaea, prokaryotic and eukaryotic viruses, fungi, protozoa, and the meiofauna. These microorganisms co-evolved with their respective hosts over millions of years, thereby establishing a mutually beneficial, symbiotic relationship on all epithelial barriers. Thus, the microbiome plays a pivotal role in virtually every aspect of mammalian physiology, particularly in the development, homeostasis, and function of the immune system. Consequently, the combination of the host genome and the microbial genome, together referred to as the metagenome, largely drives the mammalian phenotype. So far, the majority of studies have unilaterally focused on the gastrointestinal bacterial microbiota. However, recent work illustrating the impact of viruses, fungi, and protozoa on host immunity urges us towards a holistic view of the mammalian microbiome and the appreciation for its non-bacterial kingdoms. In addition, the importance of microbiota on epithelial barriers other than the gut as well as their systemic effects via microbially-derived biologically active compounds is increasingly recognized. Here, we want to provide a brief but comprehensive overview of the most important findings and the current knowledge on how microbes of all kingdoms and microbial niches shape local and systemic immunity in health and disease.

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Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies

Cited by 134 publications

References 78 publications

MYO1F regulates antifungal immunity by regulating acetylation of microtubules

MYO1F regulates antifungal immunity by regulating acetylation of microtubules

Candida albicans colonization of the gastrointestinal tract: A double-edged sword

The Mammalian Metaorganism: A Holistic View on How Microbes of All Kingdoms and Niches Shape Local and Systemic Immunity

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