Platelets Restrict the Oxidative Burst in Phagocytes and Facilitate Primary Progressive Tuberculosis

Scheuermann, Lisa; Pei, Gang; Domaszewska, Teresa; Żyła, Joanna; Oberbeck-Müller, Dagmar; Bandermann, Silke; Feng, Yonghong; Moreno, Juan Sebastian Ruiz; Opitz, Bastian; Mollenkopf, Hans-Joachim; Kaufmann, Stefan H. E.; Dorhoi, Anca

doi:10.1164/rccm.201910-2063oc

Cited by 7 publications

(7 citation statements)

References 53 publications

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“…Previous in vitro studies have demonstrated that platelets contribute to the differentiation of monocytes to the foam phenotype and switch to epithelioid and giant cells [38], and that platelets are concentrated at the site of TB lungs in a murine model [17, 39].…”

Section: Discussionmentioning

confidence: 99%

Platelets accumulate in lung lesions of tuberculosis patients and inhibit T‐cell responses and Mycobacterium tuberculosis replication in macrophages

et al. 2022

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Platelets regulate human inflammatory responses that lead to disease. However, the role of platelets in tuberculosis (TB) pathogenesis is still unclear. Here, we show that patients with active TB have a high number of platelets in peripheral blood and a low number of lymphocytes leading to a high platelets to lymphocytes ratio (PL ratio). Moreover, the serum concentration of different mediators promoting platelet differentiation or associated with platelet activation is increased in active TB. Immunohistochemistry analysis shows that platelets localise around the lung granuloma lesions in close contact with T lymphocytes and macrophages. Transcriptomic analysis of caseous tissue of human pulmonary TB granulomas, followed by Gene Ontology analysis, shows that 53 platelet activation-associated genes are highly expressed compared to the normal lung tissue. In vitro activated platelets (or their supernatants) inhibit BCG-induced T-lymphocyte proliferation and IFN-γ production. Likewise, platelets inhibit the growth of intracellular macrophages ofMycobacterium (M.) tuberculosis. Soluble factors released by activated platelets mediate both immunological and M. tuberculosis replication activities. Furthermore, proteomic and neutralisation studies (by mAbs) identify TGF-β and PF4 as the factors responsible for inhibiting T-cell response and enhancing the mycobactericidal activity of macrophages, respectively. Altogether these results highlight the importance of platelets in TB pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Platelets accumulate in lung lesions of tuberculosis patients and inhibit T‐cell responses and Mycobacterium tuberculosis replication in macrophages

et al. 2022

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“…The interaction partners of neutrophils differ in TB with infection stage, tissue site and lesion zonation. During early TB, neutrophils interact with lung-residing cells, notably alveolar macrophages, mucosal dendritic cells and pneumocytes, as well as with recruited monocytes and platelets [ 5 , 6 , 115 , 150 ]. Once infection is established, they network in addition with lymphocytes ( Figure 2 ).…”

Section: The Networking Neutrophil: Dialogues With Impact On Tb Outcomementioning

confidence: 99%

“…Accordingly, immune cells could interact with platelets in TB at various stages of the disease. Aggregates of platelets with neutrophils are present in the bronchoalveolar space of Mtb -infected mice and have also been detected in the blood of TB patients [ 150 ]. Platelets leave neutrophil kinetics, their Mtb content, viability and NET formation unchanged.…”

Section: The Networking Neutrophil: Dialogues With Impact On Tb Outcomementioning

confidence: 99%

Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense

Borkute

Woelke

Pei

et al. 2021

IJMS

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Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb–neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis.

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“…Nine modules presented strong enrichment correlated with r<0.5 and chi 2 p-value > 0.05: “platelet activation - actin binding”, “PLK1 signaling events”, “Mitochondrial Stress/Proteasome”, “Platelets”, “cell cycle”, “Erythrocytes”, “Monocytes”, “mitotic cell cycle in stimulated CD4 T cells”, “Hallmark heme metabolism” ( Figure 7B and Supplementary Table 2 ). The role of platelets has been previously described as detrimental in primary progressive TB ( 56 ).…”

Section: Resultsmentioning

confidence: 99%

Gene Set Enrichment Analysis Reveals Individual Variability in Host Responses in Tuberculosis Patients

et al. 2021

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Group-aggregated responses to tuberculosis (TB) have been well characterized on a molecular level. However, human beings differ and individual responses to infection vary. We have combined a novel approach to individual gene set analysis (GSA) with the clustering of transcriptomic profiles of TB patients from seven datasets in order to identify individual molecular endotypes of transcriptomic responses to TB. We found that TB patients differ with respect to the intensity of their hallmark interferon (IFN) responses, but they also show variability in their complement system, metabolic responses and multiple other pathways. This variability cannot be sufficiently explained with covariates such as gender or age, and the molecular endotypes are found across studies and populations. Using datasets from a Cynomolgus macaque model of TB, we revealed that transcriptional signatures of different molecular TB endotypes did not depend on TB progression post-infection. Moreover, we provide evidence that patients with molecular endotypes characterized by high levels of IFN responses (IFN-rich), suffered from more severe lung pathology than those with lower levels of IFN responses (IFN-low). Harnessing machine learning (ML) models, we derived gene signatures classifying IFN-rich and IFN-low TB endotypes and revealed that the IFN-low signature allowed slightly more reliable overall classification of TB patients from non-TB patients than the IFN-rich one. Using the paradigm of molecular endotypes and the ML-based predictions allows more precisely tailored treatment regimens, predicting treatment-outcome with higher accuracy and therefore bridging the gap between conventional treatment and precision medicine.

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Platelets Restrict the Oxidative Burst in Phagocytes and Facilitate Primary Progressive Tuberculosis

Cited by 7 publications

References 53 publications

Platelets accumulate in lung lesions of tuberculosis patients and inhibit T‐cell responses and Mycobacterium tuberculosis replication in macrophages

Platelets accumulate in lung lesions of tuberculosis patients and inhibit T‐cell responses and Mycobacterium tuberculosis replication in macrophages

Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense

Gene Set Enrichment Analysis Reveals Individual Variability in Host Responses in Tuberculosis Patients

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