An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.

Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.

Mortality beyond emergency threshold in a silent crisis- results from a population-based mortality survey in Ouaka prefecture, Central African Republic, 2020.

BACKGROUND: The Central African Republic (CAR) suffers a protracted conflict and has the second lowest human development index in the world. Available mortality estimates vary and differ in methodology. We undertook a retrospective mortality study in the Ouaka prefecture to obtain reliable mortality data. METHODS: We conducted a population-based two-stage cluster survey from 9 March to 9 April, 2020 in Ouaka prefecture. We aimed to include 64 clusters of 12 households for a required sample size of 3636 persons. We assigned clusters to communes proportional to population size and then used systematic random sampling to identify cluster starting points from a dataset of buildings in each commune. In addition to the mortality survey questions, we included an open question on challenges faced by the household. RESULTS: We completed 50 clusters with 591 participating households including 4000 household members on the interview day. The median household size was 7 (interquartile range (IQR): 4-9). The median age was 12 (IQR: 5-27). The birth rate was 59.0/1000 population (95% confidence interval (95%-CI): 51.7-67.4). The crude and under-five mortality rates (CMR & U5MR) were 1.33 (95%-CI: 1.09-1.61) and 1.87 (95%-CI: 1.37-2.54) deaths/10,000 persons/day, respectively. The most common specified causes of death were malaria/fever (16.0%; 95%-CI: 11.0-22.7), violence (13.2%; 95%-CI: 6.3-25.5), diarrhoea/vomiting (10.6%; 95%-CI: 6.2-17.5), and respiratory infections (8.4%; 95%-CI: 4.6-14.8). The maternal mortality ratio (MMR) was 2525/100,000 live births (95%-CI: 825-5794). Challenges reported by households included health problems and access to healthcare, high number of deaths, lack of potable water, insufficient means of subsistence, food insecurity and violence. CONCLUSIONS: The CMR, U5MR and MMR exceed previous estimates, and the CMR exceeds the humanitarian emergency threshold. Violence is a major threat to life, and to physical and mental wellbeing. Other causes of death speak to poor living conditions and poor access to healthcare and preventive measures, corroborated by the challenges reported by households. Many areas of CAR face similar challenges to Ouaka. If these results were generalisable across CAR, the country would suffer one of the highest mortality rates in the world, a reminder that the longstanding "silent crisis" continues.