Biology subjects

Gomes, C.

Publications and source records attributed to Gomes, C..

3 recordsLinked to original sources

bioRxiv2021

Complement Decay-Accelerating Factor is a modulator of influenza A virus lung immunopathology

Clearance of viral infections, such as SARS-CoV-2 and influenza A virus (IAV), must be fine-tuned to eliminate the pathogen without causing immunopathology. As such, an aggressive initial innate immune response favors the host in contrast to a detrimental prolonged inflammation. The complement pathway bridges innate and adaptive immune system and contributes to the response by directly clearing pathogens or infected cells, as well as recruiting proinflammatory immune cells and regulating inflammation. However, the impact of modulating complement activation in viral infections is still unclear. In this work, we targeted the complement decay-accelerating factor (DAF/CD55), a surface protein that protects cells from non-specific complement attack, and analyzed its role in IAV infections. We found that DAF modulates IAV infection in vivo, via an interplay with the antigenic viral proteins hemagglutinin (HA) and neuraminidase (NA), in a strain specific manner. Our results reveal that, contrary to what could be expected, DAF potentiates complement activation, increasing the recruitment of neutrophils, monocytes and T cells. We also show that viral NA acts on the heavily sialylated DAF and propose that it exacerbates complement activation, leading to lung immunopathology. Remarkably, this mechanism has no impact on viral loads but rather on the host resilience to infection and may have direct implications in zoonotic influenza transmissions. Author summaryExacerbated complement activation and immune deregulation are at the basis of several pathologies induced by respiratory viruses. Here, we report that complement decay-accelerating factor (DAF), which inhibits complement activation in healthy cells, increases disease severity upon Influenza A virus (IAV) infection. Remarkably, DAF interaction with IAV proteins, hemagglutinin (HA) and neuraminidase (NA), resulted in excessive complement activation and recruitment of innate and adaptive immune cells, without affecting viral loads. Furthermore, we observed that viral NA directly cleaves DAF and promotes complement activation, providing a possible link between IAV-DAF interaction and pathology. Therefore, our results unveil a novel pathway that could modulate disease severity, which may help to understand the increased pathogenicity of zoonotic and pandemic IAV infections.

microbiology↗

bioRxiv2020

Early maternal loss affects diurnal cortisol slopes in immature but not mature wild chimpanzees

In mammals, early life adversity negatively affects survival and reproductive success. A key causal mechanism is proposed by the biological embedding model which posits that adversity experienced early in life has deleterious consequences on individual physiology across the lifespan. In particular, early life adversity is expected to be a severe stressor leading to long-term alteration of the hypothalamic pituitary adrenal (HPA) axis activity. Here we tested this idea by assessing whether, as in humans, maternal loss had short and long-term impacts on orphan chimpanzee urinary cortisol levels and diurnal urinary cortisol slopes, as an indicator of the HPA axis functioning. We used 18 years of data on 50 immature and 28 mature male wild chimpanzees belonging to four communities in Tai National Park, Ivory Coast. Immature orphans who experienced early maternal loss had diurnal cortisol slopes characterised by higher early morning and late afternoon cortisol levels indicative of high activation of the HPA axis. Recently orphaned immatures had higher cortisol levels than other immatures, possibly reflecting social and nutritional stress. However, unlike in humans, we did not find significantly different cortisol profiles in orphan and non-orphan adult male chimpanzees. Our study highlights that long-term alteration of stress physiology related to early life adversity may not be viable in some wild animal populations and/or that chimpanzees, as humans, may have access to mechanisms that buffer this physiological stress, such as adoption. Our results suggest that biological embedding of altered HPA axis function is unlikely to be a mechanism contributing to the demonstrated long-term fitness consequences of maternal loss, such as reduced reproductive success, in wild long-lived mammals.

physiology↗

bioRxiv2020

Supraphysiological testosterone induces ferroptosis and activates NF-kappaB mediated immune pathways in prostate cancer through nucleophagy

The discovery that androgens play an important role in the progression of prostate cancer (PCa) has led to the development of androgen deprivation therapy as a first line of treatment against PCa. However, paradoxical growth inhibition has been observed, both experimentally and clinically, in a subset of PCa upon administration of supraphysiological levels of testosterone (SupraT). Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive PCa cells. This is initiated by induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activates nucleic acid sensors that converge on NF-kappaB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT results in increased migration of cytotoxic immune cells to tumor beds of animal xenografts and patient tumors. Collectively, our findings indicate that SupraT may inhibit a subset of PCa by activating nucleic acid sensors and downstream immune signaling.

cancer biology↗