RESUMO
Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Neoplasias , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacina BNT162 , Estudos Clínicos como Assunto , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Imunidade , SARS-CoV-2RESUMO
The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMÏ or bMÏ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMÏ whereas both Mbv and Mtb efficiently replicate in bMÏ. Specifically, we show that out of the four infection combinations, only the infection of bMÏ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMÏ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMÏ as mediators of this process.
Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Macrófagos/microbiologia , Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculose/microbiologia , Tropismo Viral/fisiologia , Animais , Bovinos , Células Gigantes , HumanosRESUMO
A striking and unexplained feature of granulomatous inflammation is its anatomical association with the lymphatic system. Accumulating evidence suggests that lymphatic tracks and granulomas may alter the function of each other. The formation of new lymphatics, or lymphangiogenesis, is an adaptive response to tumor formation, infection, and wound healing. Granulomas also may induce lymphangiogenesis which, through a variety of mechanisms, could contribute to disease outcomes in tuberculosis and sarcoidosis. On the other hand, alterations in lymph node function and lymphatic draining may be primary events which attenuate the risk and severity of granulomatous inflammation. This review begins with an introduction of granulomatous inflammation and the lymphatic system. A role of the lymphatic system in tuberculosis and sarcoidosis is then hypothesized. With a focus on lymphangiogenesis in these diseases, and on the potential for this process to promote dissemination, parallels are established with the well-established role of lymphangiogenesis in tumor biology.
Assuntos
Inflamação/patologia , Sistema Linfático/patologia , Sarcoidose/patologia , Tuberculose/patologia , Animais , Granuloma/patologia , Humanos , Linfonodos/patologia , Linfangiogênese/fisiologia , Vasos Linfáticos/patologia , Neoplasias/patologiaRESUMO
Tuberculosis (TB) is still a major global threat, killing more than one million persons each year. With the constant increase of Mycobacterium tuberculosis strains resistant to first- and second-line drugs, there is an urgent need for the development of new drugs to control the propagation of TB. Although screenings of small molecules on axenic M. tuberculosis cultures were successful for the identification of novel putative anti-TB drugs, new drugs in the development pipeline remains scarce. Host-directed therapy may represent an alternative for drug development against TB. Indeed, M. tuberculosis has multiple specific interactions within host phagocytes, which may be targeted by small molecules. In order to enable drug discovery strategies against microbes residing within host macrophages, we developed multiple fluorescence-based HT/CS phenotypic assays monitoring the intracellular replication of M. tuberculosis as well as its intracellular trafficking. What we propose here is a population-based, multi-parametric analysis pipeline that can be used to monitor the intracellular fate of M. tuberculosis and the dynamics of cellular events such as phagosomal maturation (acidification and permeabilization), zinc poisoning system or lipid body accumulation. Such analysis allows the quantification of biological events considering the host-pathogen interplay and may thus be derived to other intracellular pathogens. © 2017 International Society for Advancement of Cytometry.
Assuntos
Mycobacterium tuberculosis/metabolismo , Tuberculose/microbiologia , Animais , Antituberculosos/farmacologia , Bioensaio/métodos , Células Cultivadas , Descoberta de Drogas/métodos , Fluorescência , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Tuberculose/tratamento farmacológicoRESUMO
Mycobacterium tuberculosis produces several bacterial effectors impacting the colonization of phagocytes. Here, we report that the putative lipoprotein LppM hinders phagocytosis by macrophages in a toll-like receptor 2-dependent manner. Moreover, recombinant LppM is able to functionally complement the phenotype of the mutant, when exogenously added during macrophage infection. LppM is also implicated in the phagosomal maturation, as a lppM deletion mutant is more easily addressed towards the acidified compartments of the macrophage than its isogenic parental strain. In addition, this mutant was affected in its ability to induce the secretion of pro-inflammatory chemokines, interferon-gamma-inducible protein-10, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α. Thus, our results describe a new mycobacterial protein involved in the early trafficking of the tubercle bacillus and its manipulation of the host immune response.
Assuntos
Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno , Lipoproteínas/metabolismo , Macrófagos/microbiologia , Macrófagos/fisiologia , Mycobacterium tuberculosis/patogenicidade , Fagocitose , Fatores de Virulência/metabolismo , Animais , Proteínas de Bactérias/genética , Células Cultivadas , Deleção de Genes , Lipoproteínas/genética , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/genética , Fatores de Virulência/genéticaRESUMO
Mycobacterium tuberculosis is a successful intracellular pathogen. Numerous host innate immune responses signaling pathways are induced upon mycobacterium invasion, however their impact on M. tuberculosis replication is not fully understood. Here we reinvestigate the role of STAT3 specifically inside human macrophages shortly after M. tuberculosis uptake. We first show that STAT3 activation is mediated by IL-10 and occurs in M. tuberculosis infected cells as well as in bystander non-colonized cells. STAT3 activation results in the inhibition of IL-6, TNF-α, IFN-γ and MIP-1ß. We further demonstrate that STAT3 represses iNOS expression and NO synthesis. Accordingly, the inhibition of STAT3 is detrimental for M. tuberculosis intracellular replication. Our study thus points out STAT3 as a key host factor for M. tuberculosis intracellular establishment in the early stages of macrophage infection.