Global collaboration is the cornerstone of scientific advancement. Frontiers in Immunology has organized a series of special edition Research Topics, with the goal of highlighting the latest advancements in Infection and Immunity across the globe, showcasing the academic excellence and high-quality work of internationally recognized researchers. These collections aim to shed light on the recent progress made across the entire breadth of the Infection and Immunity field and reflect on the future challenges faced by researchers across borders. Please note, contributions to the collection are by invitation only. Please inform the Editorial Office at immunology.submissions@frontiersin.org once you are prepared to submit.

Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University

Amity Centre for Translational Research

Institut Pasteur du Cambodge

Views

Article Views

Article Downloads

Frontiers in Immunology

Microbial Immunology

Viral Immunology

Parasite Immunology

Frontiers in Microbiology

Global Excellence in Infection and Immunity: Asia and Australasia 2021

Extracellular vesicles (EVs) are nanoscale membrane-enveloped vesicles secreted by prokaryotic and eukaryotic cells, which are commonly defined as membrane vesicles (MVs) and exosomes, respectively. They play critical roles in the bacteria–bacteria and bacteria–host interactions. In infectious diseases caused by bacteria, as the first line of defense against pathogens, the macrophage polarization mode commonly determines the success or failure of the host's response to pathogen aggression. M1-type macrophages secrete pro-inflammatory factors that support microbicidal activity, while alternative M2-type macrophages secrete anti-inflammatory factors that perform an antimicrobial immune response but partially allow pathogens to replicate and survive intracellularly. Membrane vesicles (MVs) released from bacteria as a distinctive secretion system can carry various components, including bacterial effectors, nucleic acids, or lipids to modulate macrophage polarization in host–pathogen interaction. Similar to MVs, bacteria-infected macrophages can secrete exosomes containing a variety of components to manipulate the phenotypic polarization of “bystander” macrophages nearby or long distance to differentiate into type M1 or M2 to regulate the course of inflammation. Exosomes can also repair tissue damage associated with the infection by upregulating the levels of anti-inflammatory factors, downregulating the pro-inflammatory factors, and regulating cellular biological behaviors. The study of the mechanisms by which EVs modulate macrophage polarization has opened new frontiers in delineating the molecular machinery involved in bacterial pathogenesis and challenges in providing new strategies for diagnosis and therapy.

Extracellular vesicles (EVs) are nanoscale membrane-enveloped vesicles secreted by prokaryotic and eukaryotic cells, which are commonly defined as membrane vesicles (MVs) and exosomes, respectively. They play critical roles in the bacteria&#x2013;bacteria and bacteria&#x2013;host interactions. In infectious diseases caused by bacteria, as the first line of defense against pathogens, the macrophage polarization mode commonly determines the success or failure of the host&apos;s response to pathogen aggression. M1-type macrophages secrete pro-inflammatory factors that support microbicidal activity, while alternative M2-type macrophages secrete anti-inflammatory factors that perform an antimicrobial immune response but partially allow pathogens to replicate and survive intracellularly. Membrane vesicles (MVs) released from bacteria as a distinctive secretion system can carry various components, including bacterial effectors, nucleic acids, or lipids to modulate macrophage polarization in host&#x2013;pathogen interaction. Similar to MVs, bacteria-infected macrophages can secrete exosomes containing a variety of components to manipulate the phenotypic polarization of &#x201c;bystander&#x201d; macrophages nearby or long distance to differentiate into type M1 or M2 to regulate the course of inflammation. Exosomes can also repair tissue damage associated with the infection by upregulating the levels of anti-inflammatory factors, downregulating the pro-inflammatory factors, and regulating cellular biological behaviors. The study of the mechanisms by which EVs modulate macrophage polarization has opened new frontiers in delineating the molecular machinery involved in bacterial pathogenesis and challenges in providing new strategies for diagnosis and therapy.

Extracellular vesicle-mediated regulation of macrophage polarization in bacterial infections

The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decreased bacterial burden at a very early stage of Mycobacterium marinum infection, along with increased production of pro-inflammatory cytokines, such as il-1β and tnf-α. Interestingly, myeloid-lineage specific overexpression of nlrc3-like achieved the opposite effects, suggesting that the impact of nlrc3-like on the host anti-mycobacterial response is mainly due to its expression in the innate immune system. Fluorescence-activated cell sorting (FACS) and subsequent gene expression analysis demonstrated that inflammasome activation-related genes were upregulated in the infected macrophages of nlrc3-like deficient embryos. By disrupting asc, encoding apoptosis-associated speck-like protein containing a CARD, a key component for inflammasome activation, the bacterial burden increased in asc and nlrc3-like double deficient embryos compared with nlrc3-like single deficient embryos, implying the involvement of inflammasome activation in infection control. We also found extensive neutrophil infiltration in the nlrc3-like deficient larvae during infection, which was associated with comparable bacterial burden but increased tissue damage and death at a later stage that could be alleviated by administration of dexamethasone. Our findings uncovered an important role of nlrc3-like in the negative regulation of macrophage inflammasome activation and neutrophil infiltration during mycobacterial infection. This highlights the importance of a balanced innate immune response during mycobacterial infection and provides a potential molecular basis to explain how anti-inflammatory drugs can improve treatment outcomes in TB patients whose infection is accompanied by a hyperinflammatory response.

The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decreased bacterial burden at a very early stage of Mycobacterium marinum infection, along with increased production of pro-inflammatory cytokines, such as il-1β and tnf-α. Interestingly, myeloid-lineage specific overexpression of nlrc3-like achieved the opposite effects, suggesting that the impact of nlrc3-like on the host anti-mycobacterial response is mainly due to its expression in the innate immune system. Fluorescence-activated cell sorting (FACS) and subsequent gene expression analysis demonstrated that inflammasome activation-related genes were upregulated in the infected macrophages of nlrc3-like deficient embryos. By disrupting asc, encoding apoptosis-associated speck-like protein containing a CARD, a key component for inflammasome activation, the bacterial burden increased in asc and nlrc3-like double deficient embryos compared with nlrc3-like single deficient embryos, implying the involvement of inflammasome activation in infection control. We also found extensive neutrophil infiltration in the nlrc3-like deficient larvae during infection, which was associated with comparable bacterial burden but increased tissue damage and death at a later stage that could be alleviated by administration of dexamethasone. Our findings uncovered an important role of nlrc3-like in the negative regulation of macrophage inflammasome activation and neutrophil infiltration during mycobacterial infection. This highlights the importance of a balanced innate immune response during mycobacterial infection and provides a potential molecular basis to explain how anti-inflammatory drugs can improve treatment outcomes in TB patients whose infection is accompanied by a hyperinflammatory response.

Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish

Although host T cell immune responses to hepatitis B virus (HBV) have been demonstrated to have important influences on the outcome of HBV infection, the development of T cell epitope-based vaccine and T cell therapy and the clinical evaluation of specific T cell function are currently hampered markedly by the lack of validated HBV T cell epitopes covering broad patients. This study aimed to screen T cell epitopes spanning overall HBsAg, HBeAg, HBx and HBpol proteins and presenting by thirteen prevalent human leukocyte antigen (HLA)-A allotypes which gather a total gene frequency of around 95% in China and Northeast Asia populations. 187 epitopes were in silico predicted. Of which, 62 epitopes were then functionally validated as real-world HBV T cell epitopes by ex vivo IFN-γ ELISPOT assay and in vitro co-cultures using peripheral blood mononuclear cells (PBMCs) from HBV infected patients. Furthermore, the HLA-A cross-restrictions of each epitope were identified by peptide competitive binding assay using transfected HMy2.CIR cell lines, and by HLA-A/peptide docking as well as molecular dynamic simulation. Finally, a peptide library containing 105 validated epitopes which cross-binding by 13 prevalent HLA-A allotypes were used in ELISPOT assay to enumerate HBV-specific T cells for 116 patients with HBV infection. The spot forming units (SFUs) was significantly correlated with serum HBsAg level as confirmed by multivariate linear regression analysis. This study functionally validated 62 T cell epitopes from HBV main proteins and elucidated their HLA-A restrictions and provided an alternative ELISPOT assay using validated epitope peptides rather than conventional overlapping peptides for the clinical evaluation of HBV-specific T cell responses.

Although host T cell immune responses to hepatitis B virus (HBV) have been demonstrated to have important influences on the outcome of HBV infection, the development of T cell epitope-based vaccine and T cell therapy and the clinical evaluation of specific T cell function are currently hampered markedly by the lack of validated HBV T cell epitopes covering broad patients. This study aimed to screen T cell epitopes spanning overall HBsAg, HBeAg, HBx and HBpol proteins and presenting by thirteen prevalent human leukocyte antigen (HLA)-A allotypes which gather a total gene frequency of around 95% in China and Northeast Asia populations. 187 epitopes were in silico predicted. Of which, 62 epitopes were then functionally validated as real-world HBV T cell epitopes by ex vivo IFN-γ ELISPOT assay and in vitro co-cultures using peripheral blood mononuclear cells (PBMCs) from HBV infected patients. Furthermore, the HLA-A cross-restrictions of each epitope were identified by peptide competitive binding assay using transfected HMy2.CIR cell lines, and by HLA-A/peptide docking as well as molecular dynamic simulation. Finally, a peptide library containing 105 validated epitopes which cross-binding by 13 prevalent HLA-A allotypes were used in ELISPOT assay to enumerate HBV-specific T cells for 116 patients with HBV infection. The spot forming units (SFUs) was significantly correlated with serum HBsAg level as confirmed by multivariate linear regression analysis. This study functionally validated 62 T cell epitopes from HBV main proteins and elucidated their HLA-A restrictions and provided an alternative ELISPOT assay using validated epitope peptides rather than conventional overlapping peptides for the clinical evaluation of HBV-specific T cell responses.