Biology subjects

Adefisayo, O. O.

Publications and source records attributed to Adefisayo, O. O..

5 recordsLinked to original sources

bioRxiv2026

Polyketide synthase 12 is an in vivo essential source of novel mycolyl lipids in Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) is a major pathogen worldwide that infects and transmits only among humans, yet nearly all in vivo virulence research occurs in non-human hosts. To overcome this central challenge in tuberculosis research, we leveraged a dataset of more than 50,000 sequenced isolates to identify Mtb genes that that are functionally preserved during natural infection, disease causation, and transmission between humans. This whole-genome ranking identified polyketide synthase 12 (pks12 ) as an exceptionally in vivo essential gene in human tuberculosis, which we validated in zebrafish and mouse models. Though Pks12 produces a mycoketide lipid in only trace amounts, pks12 deletion severely altered the host-facing surface and arabinoglycan architecture of Mtb. This amplified effect was explained through the discovery of mannosyl-{beta}-1-phosphomycoketide monomycolate (MPMMM), which is synthesized from the known Pks12 product at higher abundance by antigen 85 mycolyltransferases. Thus, we used a new host-facing genomic-metabolomic-phenotypic approach to discover the functions of an in vivo essential Mtb gene, which controls the physical structure of the Mtb-host interface.

microbiology↗

bioRxiv2025

CCR6 is essential for effective immunity against Mycobacterium tuberculosis infection in mice

Tuberculosis (TB) is a global epidemic that has threatened human health throughout recorded history. TB disease, caused by infection with Mycobacterium tuberculosis (M.tb), is heterogeneous between individuals, and clinical TB outcomes are impacted by genetic and environmental risk factors. Infected individuals must maintain a careful balance of cytokines and chemokines following M.tb infection to eliminate or contain the bacteria without causing excessive inflammation and lung damage. The CC chemokine receptor 6 (CCR6) is expressed by several immune cell populations that are classically involved in the pathogenesis of M.tb infection. However, the precise functions of CCR6 in the context of TB disease remain underexplored. Here, we show that mice lacking the CCR6 receptor (CCR6 KO) fail to restrict bacterial burden in the lungs, leading to increased disseminated infection at 4-weeks post-infection compared to wild-type C57BL/6J (B6) mice, with a more pronounced effect in females. CCR6 KO mice also developed necrotic pulmonary lesions, phenotypically distinct from B6 mice, and produced elevated levels of pro-inflammatory cytokines and chemokines at the onset of adaptive immunity, particularly IL-17. Long-term infection experiments revealed that the absence of CCR6 enhances risk for mortality following M.tb infection, particularly in females. This study provides insights into the role of CCR6 during TB pathogenesis and establishes its importance in maintaining protective immunity against M.tb within the context of a genetically tractable mouse model that forms necrotic pulmonary granulomas.

microbiology↗

bioRxiv2025

Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity

Tuberculosis (TB) outcomes vary widely, from asymptomatic infection to mortality, yet most animal models do not recapitulate human phenotypic and genotypic variation. The genetically diverse Collaborative Cross mouse panel models distinct facets of TB disease that occur in humans and allows identification of genomic loci underlying clinical outcomes. We previously mapped a TB susceptibility locus on mouse chromosome 2. Here, we identify cathepsin Z (Ctsz) as a lead candidate underlying this TB susceptibility and show that Ctsz ablation leads to increased bacterial burden, CXCL1 overproduction, and decreased survival in mice. Ctsz disturbance within murine macrophages enhances production of CXCL1, a known biomarker of TB severity. From a Ugandan household contact study, we identify significant associations between CTSZ variants and TB disease severity. Finally, we examine patient-derived TB granulomas and report CTSZ localization within granuloma-associated macrophages, placing human CTSZ at the host-pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity.

genetics↗

bioRxiv2022

Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis.

Antibiotic resistance of Mycobacterium tuberculosis is exclusively a consequence of chromosomal mutations. Translesion synthesis (TLS) is a widely conserved mechanism of DNA damage tolerance and mutagenesis, executed by translesion polymerases such as DinBs. In mycobacteria, DnaE2 is the only known agent of TLS and the role of DinB polymerases is unknown. Here we demonstrate that mycobacterial DinB1 abets insertion and deletion frameshift mutagenesis in homo-oligonucleotide runs. DinB1 is the primary mediator of spontaneous -1 frameshift mutations in homo-oligonucleotide runs whereas DnaE2 and DinBs are redundant in DNA damage-induced -1 frameshift mutagenesis. DinB1 also promotes missense mutations conferring resistance to rifampicin, with a mutational signature distinct from that of DnaE2. These results highlight DinB1 and DnaE2 as drivers of mycobacterial genome diversification with relevance to antimicrobial resistance and host adaptation.

microbiology↗

bioRxiv2021

Division of Labor between SOS and PafBC in Mycobacterial DNA Repair and Mutagenesis

DNA repair systems allow microbes to survive in diverse environments that compromise chromosomal integrity. Pathogens such as M. tuberculosis must contend with the genotoxic host environment, which generates the mutations that underlie antibiotic resistance. Mycobacteria encode the widely distributed SOS pathway, governed by the LexA repressor, but also encode PafBC, a positive regulator of the transcriptional DNA damage response (DDR). Although the transcriptional outputs of these systems have been characterized, their full functional division of labor in survival and mutagenesis is unknown. Here we specifically ablate the PafBC or SOS pathways, alone and in combination, and test their relative contributions to repair. We find that SOS and PafBC have both distinct and overlapping roles that depend on the type of DNA damage. Most notably, we find that quinolone antibiotics and replication fork perturbation are inducers of the PafBC pathway, and that chromosomal mutagenesis is codependent on PafBC and SOS, through shared regulation of the DnaE2/ImuA/B mutasome. These studies define the complex transcriptional regulatory network of the DDR in mycobacteria and provide new insight into the regulatory mechanisms controlling the genesis of antibiotic resistance in M. tuberculosis.

microbiology↗