Nyirenda, J. | Search bioRxiv

bioRxiv2023

Spatially resolved single-cell atlas of the lung in fatal Covid19 in an African population reveals a distinct cellular signature and an interferon gamma dominated response

Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTD) including Covid19 but there is almost no data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. We used histology and high-dimensional imaging to characterise fatal lung disease in Malawian adults with (n=9) and without (n=7) Covid19, and generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved Covid19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in the Malawi cohort, by response to interferon-gamma (IFN-{gamma}) in lung-resident alveolar macrophages, in USA, European and Asian cohorts by type I/III interferon responses, particularly in blood-derived monocytes. HIV status had minimal impact on histology or immunopathology. Our study provides data resources and highlights the importance of studying the cellular mechanisms of disease in underrepresented populations, indicating shared and distinct targets for treatment.

immunology↗

bioRxiv2021

Respiratory and diarrhoeal pathogens in Malawian children hospitalized with diarrhoea and association with short-term growth

BackgroundPneumonia and diarrhoea are the leading causes of childhood mortality and morbidity worldwide. Recurrence of these common infections are one of the immediate causes of malnutrition, which puts children at risk of further infection. While studies have focused on how gut microbiota is broadly protective against respiratory infection, there has been less attention paid to the reverse relationship, of respiratory microbiota and pathogens influencing the gut, and subsequent association with growth. MethodsIn this sub-study of a prospective cohort study, 27 children (2-24 months) who tested positive for Cryptosporidium were followed up over 8 weeks. Respiratory and stool pathogens were detected using quantitative molecular methods. Nutritional outcomes were assessed as length-for-age (LAZ), weight-for-length (WLZ) and weight-for-age (WAZ) z-scores. Changes over the study period were compared using repeated analysis of variance and mixed effects model analysis. ResultsIn this period,104 sputum and stool samples were collected. All stool samples had at least one pathogen detected, with an average of 5.1 (SD 2.1) stool pathogens, compared to 84% of the sputum samples with an average 3.5 (SD1.8). Diarrhoeagenic E. coli were the most common stool pathogens (92%), followed by Cryptosporidium (52%) and Campylobacter pan (39%). In sputum, S.pneumoniae was most prevalent (84%), seconded by Rhinovirus (56%) and M. catarrhalis (50%). There was a significant change in WAZ over the follow-up period. Children who had [≥]3 GI pathogens had significantly a lower LAZ mean score at enrollment (-1.8 (SD 1.4)) and across the follow-up period. No relationship between respiratory pathogens and short-term growth was observed. Out of 49 sputum samples that had [≥]3 pathogens, 42 (85%) simultaneously had [≥]3 GI pathogens. ConclusionAmong young children hospitalized with diarrhoea, multiple gut and respiratory pathogens were prevalent over an 8-week follow-up period. The presence of more GI, but not respiratory, pathogens was significantly associated with reduced short-term growth. Author summaryThe gut-lung axis interact in both health and illness, and we aimed to see whether presence of pathogens in the GI and/or respiratory tract is associated with short-term growth. In 104 sputum and stool samples, we observed lower mean short-term growth in participants with higher number of GI, but not respiratory, pathogens.

microbiology↗