The TLR-NF-kB axis contributes to the monocytic inflammatory response against a virulent strain of Lichtheimia corymbifera , a causative agent of invasive mucormycosis

Invasive mucormycosis (IM) is a life-threatening infection caused by the fungal order Mucorales, its diagnosis is often delayed, and mortality rates range from 40-80% due to its rapid progression. Individuals suffering from hematological malignancies, diabetes mellitus, organ transplantations, and most recently COVID-19 are particularly susceptible to infection by Mucorales. Given the increase in the occurrence of these diseases, mucormycosis has emerged as one of the most common fungal infections in the last years. However, little is known about the host immune response to Mucorales. Therefore, we characterized the interaction among L. corymbifera— one of the most common causative agents of IM—and human monocytes, which are specialized phagocytes that play an instrumental role in the modulation of the inflammatory response against several pathogenic fungi. This study covered four relevant aspects of the host-pathogen interaction: i) The recognition of L. corymbifera by human monocytes. ii) The intracellular fate of L. corymbifera. iii) The inflammatory response by human monocytes against the most common causative agents of mucormycosis. iv) The main activated Pattern-Recognition Receptors (PRRs) inflammatory signaling cascades in response to L. corymbifera . Here, we demonstrate that L. corymbifera exhibits resistance to intracellular killing over 24 hours, does not germinate, and inflicts minimal damage to the host cell. Nonetheless, viable fungal spores of L. corymbifera induced early production of the pro-inflammatory cytokine IL-1β, and late release of TNF-α and IL-6 by human monocytes. Moreover, we revealed that IL-1β production predominantly depends on Toll-like receptors (TLRs) priming, especially via TLR4, while TNF-α is secreted via C-type lectin receptors (CTLs), and IL-6 is produced by synergistic activation of TLRs and CTLs. All these signaling pathways lead to the activation of NF-kB, a transcription factor that not only regulates the inflammatory response but also the apoptotic fate of monocytes during infection with L. corymbifera. Collectively, our findings provide new insights into the host-pathogen interactions, which may serve for future therapies to enhance the host inflammatory response to L. corymbifera

B Cell Recognition of Candida albicans Hyphae via TLR 2 Promotes IgG1 and IL-6 Secretion for T H 17 Differentiation

Candida albicans is usually a benign member of the human gut microbiota, but can become pathogenic under certain circumstances, for example in an immunocompromised host. The innate immune system, in particular neutrophils and macrophages, constitutes a crucial first line of defense against fungal invasion, however adaptive immunity may provide long term protection and thus allow vaccination of at risk patients. While T H 1 and T H 17 cells are important for antifungal responses, the role of B cells and antibodies in protection from C. albicans infection is less well defined. In this study, we show that C. albicans hyphae but not yeast, as well as fungal cell wall components, directly activate B cells via MyD88 signaling triggered by Toll- like receptor 2, leading to increased IgG1 production. While Dectin-1 signals and specific recognition by the B cell receptor are dispensable for B cell activation in this system, TLR2/MyD88 signals cooperate with CD40 signals in promoting B cell activation. Importantly, recognition of C. albicans via MyD88 signaling is also essential for induction of IL-6 secretion by B cells, which promotes T H 17 polarization in T-B cell coculture experiments. B cells may thus be activated directly by C. albicans in its invasive form, leading to production of antibodies and T cell help for fungal clearance

The relationship between testosterone and long-distance calling in wild male chimpanzees

Abstract: Long-distance calling is a common behaviour in animals, which has various important social functions. At a physiological level, calling is often mediated by gonadal hormones such as testosterone (T), particularly when its function is linked to intra-sexual competition for mates or territory. T also plays an important role in the development of vocal characteristics associated with dominance in humans. However, the few available studies of T and vocal behaviour in non-human primates suggest that in primates, T has less influence on call production than in other animals. We tested this hypothesis by studying the relationship between T concentrations and pant-hooting in wild male chimpanzees (Pan troglodytes schweinfurthii) of the Kanyawara community in the Kibale National Park, Uganda. We found three kinds of correlation. Hourly T averages were positively associated with hourly rates of pant-hooting. Monthly T levels were likewise correlated with monthly rates of pant-hooting after controlling for other influences such as fission-fusion rates. Finally, males with high T levels had higher peak frequency at the start of the call climax. These results suggest that T affects the production of pant-hoots in chimpanzees. This implies that the pant-hoot call plays a role in male-male competition. We propose that even in cognitively sophisticated species, endocrine mechanisms can contribute to regulating vocal production. Significance statement: Many animals produce long-distance calls. The production of these calls is often modulated by gonadal hormones such as testosterone, especially if the calls are involved in competition between males for mates or territory. However, comparatively little is known about the influence of testosterone over the vocal behaviour of non-human primates, especially among great apes. In this study, we examined the relationship between testosterone and pant-hooting in wild male chimpanzees. We found that testosterone levels were associated with pant-hoot rates and one acoustic feature of the call. More specifically, males pant-hooted more often and produced pant-hoots with higher peak frequencies during periods of elevated testosterone levels. These results imply that gonadal hormones are involved in regulating vocal behaviour in chimpanzees and support the view that pant-hoots play a role in male-male competition