Coronavirus disease 2019 (COVID-19) has a broad range of clinical manifestations, highlighting the need for specific diagnostic tools to predict disease severity and improve patient prognosis. ...Recently, calprotectin (S100A8/A9) has been proposed as a potential biomarker for COVID-19, as elevated serum S100A8/A9 levels are associated with critical COVID-19 cases and can distinguish between mild and severe disease states. S100A8/A9 is an alarmin that mediates host proinflammatory responses during infection and it has been postulated that S100A8/A9 modulates the cytokine storm; the hallmark of fatal COVID-19 cases. However, it has yet to be determined if S100A8/A9 is a bona-fide biomarker for COVID-19. S100A8/A9 is widely implicated in a variety of inflammatory conditions, such as cystic fibrosis (CF) and chronic obstructive pulmonary disorder (COPD), as well as pulmonary infectious diseases, including tuberculosis and influenza. Therefore, understanding how S100A8/A9 levels correlate with immune responses during inflammatory diseases is necessary to evaluate its candidacy as a potential COVID-19 biomarker. This review will outline the protective and detrimental roles of S100A8/A9 during infection, summarize the recent findings detailing the contributions of S100A8/A9 to COVID-19 pathogenesis, and highlight its potential as diagnostic biomarker and a therapeutic target for pulmonary infectious diseases, including COVID-19.
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•Calprotectin (S100A8/A9) as a potential biomarker for COVID-19 can distinguish between mild and severe disease states.•S100A8/A9 is an alarmin that mediates host proinflammatory responses during infection.•Protective and detrimental roles of S100A8/A9 during infection.•Potential as diagnostic biomarker and a therapeutic target for pulmonary infectious diseases, including COVID-19.
Chemokines and cytokines are critical for initiating and coordinating the organized and sequential recruitment and activation of cells into Mycobacterium tuberculosis-infected lungs. Correct ...mononuclear cellular recruitment and localization are essential to ensure control of bacterial growth without the development of diffuse and damaging granulocytic inflammation. An important block to our understanding of TB pathogenesis lies in dissecting the critical aspects of the cytokine/chemokine interplay in light of the conditional role these molecules play throughout infection and disease development. Much of the data highlighted in this review appears at first glance to be contradictory, but it is the balance between the cytokines and chemokines that is critical, and the "goldilocks" (not too much and not too little) phenomenon is paramount in any discussion of the role of these molecules in TB. Determination of how the key chemokines/cytokines and their receptors are balanced and how the loss of that balance can promote disease is vital to understanding TB pathogenesis and to identifying novel therapies for effective eradication of this disease.
Mycobacterium tuberculosis (Mtb) acquires resistance to the frontline antibiotic rifampicin through chromosomal mutations in a subunit of the Mtb RNA polymerase.Drug resistance mutations in Mtb are ...associated with a broad range of bacterial changes, including transcriptional alterations, and differences in bacterial cell wall composition and metabolic processes.Patients with drug-resistant Mtb infection display altered immune responses with limited immune cell activation and increased accumulation of immune regulatory cells.Animal studies suggest that the presence of drug resistance mutations in Mtb affects host–pathogen interactions and results in different immune parameters.
Rifampicin drug resistance-conferring mutations may have profound impact on host–pathogen interactions during Mtb infection through broad changes to mycobacterial structure and physiology. Interactions of altered DR bacteria with immune cells might help explain certain dysregulated immune responses observed in patients with DR TB. Determining how host immunity is altered during DR Mtb infection can allow for a greater understanding of clinical manifestations in patients with DR TB, enabling the development of rational host-directed candidate therapeutics targeting DR TB.
Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global dissemination of drug resistance across Mycobacterium tuberculosis (Mtb) strains, causative of TB, resulted in an estimated 450 000 cases of drug-resistant (DR) TB in 2021. Dysregulated immune responses have been observed in patients with multidrug resistant (MDR) TB, but the effects of drug resistance acquisition and impact on host immunity remain obscure. In this review, we compile studies that span aspects of altered host–pathogen interactions and highlight research that explores how drug resistance and immunity might intersect. Understanding the immune processes differentially induced during DR TB would aid the development of rational therapeutics and vaccines for patients with MDR TB.
Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global dissemination of drug resistance across Mycobacterium tuberculosis (Mtb) strains, causative of TB, resulted in an estimated 450 000 cases of drug-resistant (DR) TB in 2021. Dysregulated immune responses have been observed in patients with multidrug resistant (MDR) TB, but the effects of drug resistance acquisition and impact on host immunity remain obscure. In this review, we compile studies that span aspects of altered host–pathogen interactions and highlight research that explores how drug resistance and immunity might intersect. Understanding the immune processes differentially induced during DR TB would aid the development of rational therapeutics and vaccines for patients with MDR TB.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world's population. Among these infections, clinical isolates belonging to the W-Beijing appear to ...be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered "hypervirulent" as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1β through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.
Tuberculosis (TB) results from an interaction between a potent immune response and a chronically persistent pathogen. The ability of Mycobacterium tuberculosis (Mtb) to induce a strong immune ...response while being able to resist the ability of the host to clear bacteria provides an excellent tool with which to investigate the role of specific cytokine pathways on the induction, expansion, and control of the effector T-cell response. In this review, the role of interleukin-12p40 (IL-12p40), IL-12p70, IL-23, and IL-27 in the immune response to Mtb are described. We show that IL-12(p40)₂ acts to mediate the activation of dendritic cells to become responsive to homeostatic chemokines. We also show that IL-12p70 is required for the optimal interferon-γ (IFN-γ) T-cell response, which is required for control of Mtb growth. IL-23 can induce IFN-γ responses in the lung if IL-12 is not present, but its major role is in supporting the IL-17 response within the lung. Neither IL-23 nor IL-17 is required for early control of Mtb in the lung. IL-23 and IL-17, however, can be instrumental in vaccine-induced protection. Finally, IL-27 limits protective immunity in the lung, but it is also required for long-term survival. These cytokines are therefore key players in the immune response to TB.
Over a quarter of the world’s population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18% of recurrent cases of TB are ...multidrug-resistant (MDR) or rifampicin-resistant. Recent evidence has shown that certain drug-resistant strains of Mtb modulate host metabolic reprogramming, and therefore immune responses, during infection. However, it remains unclear how widespread these mechanisms are among circulating MDR Mtb strains and what impact drug-resistance-conferring mutations have on immunometabolism during TB. While few studies have directly addressed metabolic reprogramming in the context of drug-resistant Mtb infection, previous literature examining how drug-resistance mutations alter Mtb physiology and differences in the immune response to drug-resistant Mtb provides significant insights into how drug-resistant strains of Mtb differentially impact immunometabolism.
Mtb infection drives metabolic reprogramming for induction of protective immune responses.Drug resistance in Mtb is associated with changes in lipid and protein expression that can mediate differential host–pathogen interactions.Rifampicin-resistant Mtb strains carrying the H445Y mutation modulate host metabolic reprogramming and alter downstream immune responses.
Highlights • Chemokines govern cell influx to Mtb -infected lungs and are critical for TB control. • Productive granuloma formation is tightly regulated by lung-secreted chemokines. • Chemokine ...dysregulation can shift the balance from protection to inflammation. • Host, pathogen and environmental factors can impact chemokine secretion in the TB lung.
Inflammatory stimuli reprogram innate immune cells to generate rigorous responses to future challenge with heterologous stimuli through trained immunity. Li et al. show that training of hematopoietic ...stem cells (HSCs) in the bone marrow primes cells to generate more inflammatory myeloid progeny and, thereby, mechanistically links inflammatory comorbidities.
Abstract The T helper type 17 (Th17) lineage of CD4+ T-cells produce several effector molecules including IL-17A, IL-17F, IL-21, and IL-22. In addition to CD4+, αβ T-cells, these cytokines can be ...produced by natural killer and γδ T-cells. These effector cytokines can be produced rapidly upon infection at mucosal sites and evidence to date strongly implicates that this arm of the immune system plays a critical role in mucosal immunity to many extracellular pathogens. Moreover these cytokines can also coordinate adaptive immunity to some intracellular pathogens. In this review, we will highlight recent progress in our understanding of these cytokines, and mechanisms of their effector function in the mucosa.
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