Human respiratory syncytial virus (RSV) is the most common cause of viral bronchiolitis and pneumonia in infants and children worldwide. Inflammation induced by RSV infection is responsible for its hallmark manifestation of bronchiolitis and pneumonia. The cellular debris created through lytic cell death of infected cells is a potent initiator of this inflammation. Macrophages are known to play a pivotal role in the early innate immune and inflammatory response to viral pathogens. However, the lytic cell death mechanisms associated with RSV infection in macrophages remains unknown. Two distinct mechanisms involved in lytic cell death are pyroptosis and necroptosis. Our studies revealed that RSV induces lytic cell death in macrophages via both of these mechanisms, specifically through the ASC (Apoptosis-associated speck like protein containing a caspase recruitment domain)-NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome activation of both caspase-1 dependent pyroptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), as well as a mixed lineage kinase domain like pseudokinase (MLKL)-dependent necroptosis. In addition, we demonstrated an important role of reactive oxygen species (ROS) during lytic cell death of RSV-infected macrophages.

Critically ill COVID-19 patients display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We inoculated and treated human macrophage cell line THP-1 with SARS-CoV-2 and purified, glycosylated, soluble SARS-CoV-2 spike protein S1 subunit (S1) to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication or viral entry, virus exposure resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that extracellular soluble S1 protein is a key viral component inducing pro-inflammatory responses in macrophages, independent of virus replication. Thus, virus- or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

Various reports allude to negative clinical outcomes in tuberculosis (TB) and COVID-19 co-infected patients {1-4}. Mechanistic studies to address this co-infection face significant challenges, for example, experimental models simultaneously permissive to both pathogens that could recapitulate the lung environment, and host immune responses. The study of Sheerin et al. aims to answer some of these mechanistic questions by exploiting available transcriptomic data for TB and COVID-19. The study identified transcriptomic signatures associated with COVID-19 disease severity by meta-analysis and evaluated these signatures in transcriptomic data from TB patients. The authors found that many severe COVID-19 transcriptomic profiles were present in active/progressing TB transcriptomes. These shared transcriptomic profiles were composed of distinct cellular pathways, suggesting that severe COVID-19 and active TB each elicit overlapping host responses that may contribute to enhanced risk of severe illness in co-infected patients. The study also identifies specific immune cells enriched in COVID-19 and TB patients, which the authors argue may drive hyperinflammatory responses during co-infection. Although with limited data, this study suggests that prior TB infection may facilitate macrophage infection with SARS-CoV-2. This study offers a glimpse at overlapping cellular processes provoked by each individual pathogen and proposes that these may coalesce during co-infection and influence clinical outcomes.

One of the hallmarks of Tuberculosis infection is the formation of complex cellular structures in the lungs called granulomas. Granulomas are heterogenous in their ability to control Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, with some able to restrict or even clear the bacteria and others permitting high bacterial burdens. The factors that define the composition, function, and trajectories of these granulomas are complex and still poorly understood. Gideon and colleagues dissect and analyse these granulomas from infected macaques using different techniques: longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing and measurement of bacterial loads (plating for colony forming units and determining chromosomal counts). Bacterial burdens were then correlated with cellular composition and immune response using single cell RNA sequencing. This work identifies two main types of granulomas: i) early forming that were associated with higher bacterial burden and enriched for mast cells and plasma cells with activation of repair pathways and ii) granulomas that arose later in the infection that were much more efficient in Mtb control and characterized by Type 1-Type 17 cellular profile rich in cytotoxic T/NK cells and pro-inflammatory signalling. The RNA-seq data has been posted online (see here) and could be a valuable resource for scientists interested in identifying host-directed therapeutic targets.