Biology subjects

Samhadaneh, N. M.

Publications and source records attributed to Samhadaneh, N. M..

4 recordsLinked to original sources

bioRxiv2025

Gastrointestinal colonization as a source of Staphylococcus aureus in atopic dermatitis

Atopic dermatitis (AD) is a prevalent inflammatory skin disease with complex pathogenesis. Both skin and gut microbiota influence AD, with Staphylococcus aureus, in particular, exacerbating the disease. However, the relationship between S. aureus colonization in the gut and skin, and whether it affects AD, remains unclear. Using a combination of culture-based methods, microbiome analysis, and genome sequencing of S. aureus from multiple body sites of children with and without AD, we found that the gut represents a major reservoir of genetically diverse S. aureus that is transmitted to the skin, including mutants associated with worse disease. We validated this association between S. aureus gastrointestinal colonization and AD in an independent human cohort and demonstrated its direct effect on disease in an infantile AD mouse model, wherein S. aureus gastrointestinal colonization worsened skin inflammation. Overall, this study identifies a previously unrecognized S. aureus reservoir, with implications for microbiota-targeting therapies in AD.

microbiology↗

bioRxiv2024

Identification of a proteolysis regulator for an essential enzyme in Mycobacterium tuberculosis

In Mycobacterium tuberculosis proteins that are post-translationally modified with Pup, a prokaryotic ubiquitin-like protein, can be degraded by proteasomes. While pupylation is reversible, mechanisms regulating substrate specificity have not been identified. Here, we identify the first depupylation regulators: CoaX, a pseudokinase, and pantothenate, an essential, central metabolite. In a {Delta}coaX mutant, pantothenate synthesis enzymes were more abundant, including PanB, a substrate of the Pup-proteasome system. Media supplementation with pantothenate decreased PanB levels in a coaX and Pup-proteasome-dependent manner. In vitro, CoaX accelerated depupylation of Pup[~]PanB, while addition of pantothenate inhibited this reaction. Collectively, we propose CoaX contributes to proteasomal degradation of PanB by modulating depupylation of Pup[~]PanB in response to pantothenate levels. One Sentence SummaryA pseudo-pantothenate kinase regulates proteasomal degradation of a pantothenate synthesis enzyme in M. tuberculosis.

microbiology↗

bioRxiv2023

Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity

Mycobacterium tuberculosis is a major human pathogen and the causative agent of tuberculosis disease. M. tuberculosis is able to persist in the face of host-derived antimicrobial molecules nitric oxide and copper. However, M. tuberculosis with defective proteasome activity is highly sensitive to nitric oxide and copper, making the proteasome an attractive target for drug development. Previous work linked nitric oxide susceptibility with the accumulation of para-hydroxybenzaldehyde in M. tuberculosis mutants with defective proteasomal degradation. In this study, we found that para-hydroxybenzaldehyde accumulation was also responsible for copper sensitivity in these strains. We showed that exogenous addition of para-hydroxybenzaldehyde to wild-type M. tuberculosis cultures sensitized bacteria to copper to a degree similar to that of a proteasomal degradation mutant. We determined that para-hydroxybenzaldehyde reduced the production and function of critical copper resistance proteins of the regulated in copper repressor (RicR) regulon. Further, we extended these Cu-sensitizing effects to an aldehyde that M. tuberculosis may face within the macrophage. Collectively, this study is the first to mechanistically propose how aldehydes can render M. tuberculosis susceptible to an existing host defense and could support a broader role for aldehydes in controlling M. tuberculosis infections. IMPORTANCEM. tuberculosis is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for M. tuberculosis infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control M. tuberculosis infections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increase M. tuberculosis susceptibility to copper, an established antibacterial metal used by immune cells to control M. tuberculosis and other microbes. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes may help control bacterial infections, making aldehydes a previously unappreciated antimicrobial defense.

microbiology↗

bioRxiv2022

Aldehyde inactivation of the RicR regulon sensitizes Mycobacterium tuberculosis to copper

Mycobacterium tuberculosis is a major human pathogen and the causative agent of tuberculosis disease. While M. tuberculosis can persist in the presence of host-derived antimicrobials like nitric oxide and copper, bacteria defective for proteasome activity are highly sensitive to these molecules, making the proteasome an attractive target for drug development. Previous work linked nitric oxide susceptibility with the accumulation of at least one aldehyde in an M. tuberculosis mutant lacking proteasomal degradation. In this study, we show that this aldehyde accumulation is also responsible for copper sensitivity in this strain. Furthermore, we show the exogenous addition of aldehydes to wild-type M. tuberculosis cultures sensitizes bacteria to copper. We determined that aldehydes directly affect the activity of two members of the RicR (regulated in copper repressor) regulon, resulting in the reduced production and function of critical copper-responsive proteins. This study is the first to mechanistically describe how aldehydes can render M. tuberculosis susceptible to an existing host defense, and could support a broader role for aldehydes in controlling M. tuberculosis infections. IMPORTANCEM. tuberculosis is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for M. tuberculosis infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control M. tuberculosis infections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increase M. tuberculosis susceptibility to copper. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes target critical bacterial survival pathways, making aldehydes a previously unappreciated antimicrobial defense.

microbiology↗