Biology subjects

Nakiyingi, L.

Publications and source records attributed to Nakiyingi, L..

3 recordsLinked to original sources

bioRxiv2026

Distinct transcriptional remodeling of immune and metabolic pathways in severe undernutrition during latent tuberculosis infection does not consistently predict tuberculosis progression across independent cohorts

Background: Undernutrition increases tuberculosis (TB) risk, but whether severe undernutrition during latent TB infection (LTBI) produces blood transcriptional changes that resemble active disease or identify future TB remains unclear. Methods: We reanalyzed whole-blood RNA sequencing from adults with LTBI in GSE152218, comparing severe undernutrition (BMI <16 kg/m2; n=16) with adequate nutrition (BMI >=18.5 kg/m2; n=11). Genes and Reactome pathways were evaluated. A seven-module summary was compared with active TB among severely undernourished adults and tested prospectively in GSE79362 and GC6-74/GSE94438 after pathway-representation assessment. Results: No genes reached FDR <0.05 in the primary model; two did only in sensitivity analysis. In contrast, 241 Reactome pathways were significant and directionally concordant in both models (NES rho=0.954), including complement/Fc-receptor, B-cell, phospholipid/phagocytosis, neutrophil, vascular, autophagy, and cytokine-signaling pathways. Most changed opposite to the active-TB comparison (178/241; pathway rho=-0.390). The seven-module score was unrelated to baseline progression in GSE79362 (adjusted OR per SD=1.090; P=0.6922). In GC6, four modules met the prespecified representation criterion; their baseline score was inversely associated with progression (adjusted OR per SD=0.711; P=0.0218), but secondary and longitudinal analyses were non-confirmatory. Conclusions: Severe undernutrition during LTBI is associated with reproducible immune- and metabolism-related transcriptional remodeling that differs from active-TB biology and does not consistently identify future TB progression.

molecular biology↗

bioRxiv2026

Novel human monoclonal antibodies with enhanced sensitivity for lipoarabinomannan antigens present in urines of TB patients

Lipoarabinomannan (LAM) is a useful biomarker for detection of M. tuberculosis infection and disease. Related antigens can be detected in urine samples of TB patients by combinations of monoclonal antibodies (mAbs) directed against specific epitopes expressed in LAM. While sensitive for samples from patients with active TB disease who have HIV-1 co-infections, these assays are less effective for other populations, and there is therefore a need for more sensitive antibodies that can improve the sensitivity of these assays. Here we characterize the antigen and epitope specificities, sequence diversity and isotype dependencies of eight LAM-specific human mAbs that target five distinct arabinose- and mannose-dependent epitopes present in LAM and lipoarabinomannan (LM). Whereas all of the mAbs recognized ManLAM, only a few, including A194-01, consistently detected antigens in TB+ urine samples. Converting A194-01 from the IgG1 to the IgM isotype resulted in broader recognition of poly-Ara glycan epitopes, and increased sensitivity for clinical antigens when combined with several capture reagents, including RU95-C1, a novel antibody targeting the mannan domain of LAM. These results define novel epitopes that are differentially expressed in bacterial and urinary forms of LAM, and identify novel antibody combinations which possess enhanced diagnostic utility for clinical forms of LAM.

immunology↗

bioRxiv2022

Mycobacterium tuberculosis disease associates with higher HIV-1-specific antibody responses

Mycobacterium tuberculosis (Mtb) can enhance immune responses against unrelated pathogens. Although Mtb is the most common co-infection in people living with HIV (PWH), there has been no examination of its impact on HIV-1 immune responses. Plasma neutralization and antibody dependent cellular cytotoxicity (ADCC) was compared among PWH and Mtb disease (PWH/Active Mtb) and PWH/No Mtb both prior to and after antiretroviral treatment (ART) and completion of Mtb therapy. We assessed HIV-1 sequences, total antibody quantities and isotypes, and plasma cytokine levels to ascertain mechanisms that affect humoral responses. HIV-1 neutralizing antibodies (nAbs) were broader and more potent in PWH/Active Mtb as compared to PWH/No Mtb, and nAbs increased among PWH who developed Mtb after ART initiation. ADCC was also higher in the PWH who had Mtb disease after starting ART. PWH/Active Mtb as compared to PWH/No Mtb had unique HIV-1 envelope sequence motifs associated with neutralization resistance further implying differences in humoral selection. The Mtb-linked antibody augmentation associated with elevated plasma cytokine levels important for B cells and antibody production, namely interleukin-6, a proliferation-inducing ligand (APRIL), and B-cell activating factor (BAFF). Increased plasma virus levels, greater HIV-1 envelope diversity, higher levels of all antibodies, and cross-reactive responses did not explain the enhanced HIV-1 humoral responses in those with Mtb. Mtb disease enhances HIV-1 humoral responses likely by perturbing pathways important for antibody production in lymphoid tissue that has both pathogens. These findings have implications for using antibody-based therapies and inducing optimal HIV-1 antibody responses. Author SummaryMycobacterium tuberculosis (Mtb) is the most common infection among people with HIV (PWH) in the world. Mtb infection can enhance immune responses against unrelated pathogens. Previous studies have not examined the impact of Mtb disease on HIV antibodies in PWH. This information has importance for future strategies aimed at enhancing HIV antibody responses in naive individuals or PWH. We show that HIV neutralizing antibodies and antibody-dependent cellular cytotoxicity are broader and more potent in PWH in the presence as compared to the absence of Mtb disease. PWH and Mtb disease as compared to those without Mtb also harbor unique HIV envelope sequences, which further indicates that there is differential antibody selection pressure. The Mtb linked HIV antibody enhancement associated with specific mediators important for B cell and antibody development. Importantly, the Mtb mediated HIV antibody augmentation was not due to cross-reactivity, a generalized increase in all antibodies, or a higher level, more diverse, or longer duration of antigen exposure. We speculate that more potent HIV antibodies arise in lymphatic tissue that harbors both Mtb and HIV. Our findings have implications for both future uses of HIV antibodies as prophylaxis or treatment and strategies aimed inducing better HIV antibody responses.

microbiology↗