Biology subjects

Limon, G.

Publications and source records attributed to Limon, G..

2 recordsLinked to original sources

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↗

bioRxiv2021

Viral dynamics and immune responses to foot-and-mouth disease virus in African buffalo (Syncerus caffer).

Foot-and-mouth disease (FMD) is one of the most important livestock diseases restricting international trade. While it is clear that African buffalo (Syncerus caffer) act as the main wildlife reservoir, viral and immune response dynamics during FMD virus acute infection have not been described before in this species. We used experimental needle inoculation and contact infections with three Southern African Territories serotypes to assess clinical, virological and immunological dynamics for thirty days post infection. Clinical FMD in the needle inoculated buffaloes was mild and characterised by pyrexia. Despite the absence of generalised vesicles, all contact animals were readily infected with their respective serotypes within the first 2-9 days after being mixed with needle challenged buffaloes. Irrespective of the route of infection or serotype there were positive associations between the viral loads in blood and the induction of host innate pro-inflammatory cytokines and acute phase proteins. Viral loads in blood and tonsils were tightly correlated during the acute phase of the infection, however, viraemia significantly declined after a peak at 4 days post infection (dpi), which correlated with the presence of detectable neutralising antibodies. In contrast, infectious virus was isolated in the tonsils until the last sampling point (30 dpi) in most animals. The pattern of virus detection in serum and tonsil swabs was similar for all three serotypes in the direct challenged and contact challenged animals. We have demonstrated for the first time, that African buffalo are indeed systemically affected by FMD virus and clinical FMD in buffalo is characterized by a transient pyrexia. Despite the lack of FMD lesions, infection of African buffalo was characterised by high viral loads in blood and oropharynx, rapid and strong host innate and adaptive immune responses and high transmissibility.

zoology↗