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Host Immune Responses to Intracellular Pathogens

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A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Immunological Responses and Immune Defense Mechanisms".

Deadline for manuscript submissions: closed (15 December 2024) | Viewed by 20428

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Prof. Dr. Sergio Costa Oliveira

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Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
Interests: innate immunity; inflammasomes; cytosolic sensors; STING; intracellular infections
Special Issues, Collections and Topics in MDPI journals

Dr. Guillermo Giambartolomei

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Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
Interests: innate immunity; intracellular infections; immunopathology of CNS
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Innate immunity is the first arm of the immune system to be triggered in host defense against intracellular pathogens. Later, the adaptive immune response is activated and plays a major role in protection against infections; however, further studies are required to elucidate this complex circuit by which the host immune system recognizes and eliminates intracellular pathogens. Of particular interest is how intracellular pathogens escape innate immune recognition. These aspects of the host–parasite relationship will be discussed in this Special Issue, and the findings will help to advance the comprehension of host immune responses as well as pathogenesis and contribute to the future development of drugs or vaccines with which to control infections. For this Special Issue of Pathogens, we invite you to submit a review or research article related to host immune responses, inflammation, T and B cell responses, vaccine development, immune evasion, and the pathology as well as pathogenesis of bacterial, viral, fungal, or protozoan intracellular infections. We look forward to your contribution.

Prof. Dr. Sergio Costa Oliveira
Dr. Guillermo Giambartolomei
Guest Editors

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Keywords

innate immunity
adaptive immunity
intracellular infections
bacteria
virus
protozoan parasites

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Published Papers (9 papers)

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Research

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10 pages, 1462 KiB

Open AccessArticle

The Leishmania Skin Test Predicts Clinic-Immunologic and Therapeutic Outcomes in Cutaneous Leishmaniasis

by Luiz H. Guimarães, Evelyn Zacarias, Sandra T. Nolasco, Almério N. Filho, Jamile Lago, Paulo R. L. Machado, Joyce Oliveira, Lucas P. Carvalho, Augusto Carvalho, Edgar M. Carvalho and Sérgio Arruda

Pathogens 2024, 13(11), 1018; https://doi.org/10.3390/pathogens13111018 - 19 Nov 2024

Viewed by 1236

Abstract

Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, is closely associated with a severe form of the disease, indicated by a positive Leishmania skin test (LST) that assesses and reflects the presence of immune T cells specific to Leishmania antigens. In this study, we compare the clinical, immunologic, and histopathologic features between Leishmania skin test-positive (LST+) and Leishmania skin test-negative (LST-) in CL. Compared to LST+ patients, LST- patients had larger lesions and had been sicker for longer, presented with more instances of therapeutic failure with meglumine antimonate, (MA) and the healing times were higher than LST+. While granulomas were less frequent and the parasite load was higher in LST-, there were more CD8+ T cells and an enhanced production of Granzyme B in the supernatants of biopsies from LST- subjects. This study shows that in LST-, an impairment in Th1 immune response is associated with a high parasite burden, and the pathology is mediated by CD8+ T cells and the enhanced production of Granzyme B. The abnormalities in the immunologic response in LST- patients lead to a more severe disease with a high rate of failure to therapy. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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16 pages, 2853 KiB

Open AccessArticle

E3 Ubiquitin Ligase Smurf1 Regulates the Inflammatory Response in Macrophages and Attenuates Hepatic Damage during Betacoronavirus Infection

by Luiz P. Souza-Costa, Felipe R. S. Santos, Jordane C. Pimenta, Celso M. Queiroz-Junior, Fernanda L. Tana, Danielle C. Teixeira, Manoela G. G. Couto, Natalia F. M. Oliveira, Rafaela D. Pereira, Vinicius A. Beltrami, Pedro A. C. Costa, Larisse S. B. Lacerda, Josiane T. Andrade-Chaves, Pedro P. G. Guimarães, Renato S. Aguiar, Mauro M. Teixeira, Vivian V. Costa and Luis H. Franco

Pathogens 2024, 13(10), 871; https://doi.org/10.3390/pathogens13100871 - 3 Oct 2024

Viewed by 1628

Abstract

The E3 ubiquitin ligase Smurf1 catalyzes the ubiquitination and proteasomal degradation of several protein substrates related to inflammatory responses and antiviral signaling. This study investigated the role of Smurf1 in modulating inflammation induced by Betacoronavirus infection. Bone marrow-derived macrophages (BMDMs) from C57BL/6 (wild-type) or Smurf1-deficient (Smurf1^−/−) mice were infected with MHV-A59 to evaluate the inflammatory response in vitro. Smurf1 was found to be required to downregulate the macrophage production of pro-inflammatory mediators, including TNF, and CXCL1; to control viral release from infected cells; and to increase cell viability. To assess the impact of Smurf 1 in vivo, we evaluated the infection of mice with MHV-A59 through the intranasal route. Smurf1^−/− mice infected with a lethal inoculum of MHV-A59 succumbed earlier to infection. Intranasal inoculation with a 10-fold lower dose of MHV-A59 resulted in hematological parameter alterations in Smurf1^−/− mice suggestive of exacerbated systemic inflammation. In the lung parenchyma, Smurf1 expression was essential to promote viral clearance, downregulating IFN-β mRNA and controlling the inflammatory profile of macrophages and neutrophils. Conversely, Smurf1 did not affect IFN-β mRNA regulation in the liver, but it was required to increase TNF and iNOS expression in neutrophils and decrease TNF expression in macrophages. In addition, Smurf1^−/− mice exhibited augmented liver injuries, accompanied by high serum levels of alanine aminotransferase (ALT). These findings suggest that Smurf1 plays a critical role in regulating the inflammatory response in macrophages and attenuating systemic inflammation during Betacoronavirus infection. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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11 pages, 4869 KiB

Open AccessArticle

Long-Lasting, Fine-Tuned Anti-Tumor Activity of Recombinant Listeria monocytogenes Vaccine Is Controlled by Pyroptosis and Necroptosis Regulatory and Effector Molecules

by Abolaji S. Olagunju, Andrew V. D. Sardinha and Gustavo P. Amarante-Mendes

Pathogens 2024, 13(10), 828; https://doi.org/10.3390/pathogens13100828 - 25 Sep 2024

Cited by 1 | Viewed by 1566

Abstract

One of the main objectives of developing new anti-cancer vaccine strategies is to effectively induce CD8+ T cell-mediated anti-tumor immunity. Live recombinant vectors, notably Listeria monocytogenes, have been shown to elicit a robust in vivo CD8+ T-cell response in preclinical settings. Significantly, it has been demonstrated that Listeria induces inflammatory/immunogenic cell death mechanisms such as pyroptosis and necroptosis in immune cells that favorably control immunological responses. Therefore, we postulated that the host’s response to Listeria-based vectors and the subsequent induction of CD8+ T cell-mediated immunity would be compromised by the lack of regulatory or effector molecules involved in pyroptosis or necroptosis. To test our hypothesis, we used recombinant L. monocytogenes carrying the ovalbumin gene (LM.OVA) to vaccinate wild-type (WT), caspase-1/11^−/−, gsdmd^−/−, ripk3^−/−, and mlkl^−/− C57Bl/6 mice. We performed an in vivo cytotoxicity assay to assess the efficacy of OVA-specific CD8+ T lymphocytes in eliminating target cells in wild-type and genetically deficient backgrounds. Furthermore, we evaluated the specific anti-tumor immune response in mice inoculated with the B16F0 and B16F0.OVA melanoma cell lines. Our findings demonstrated that while caspase-1/11 and GSDMD deficiencies interfere with the rapid control of LM.OVA infection, neither of the KOs seems to contribute to the early activation of OVA-specific CTL responses. In contrast, the individual deficiency of each one of these proteins positively impacts the generation of long-lasting effector CD8+ T cells. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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15 pages, 2798 KiB

Open AccessArticle

Alterations of Plasma Biochemical and Immunological Parameters and Spatiotemporal Expression of TLR2 and TLR9 in Gibel Carp (Carassius auratus gibelio) after CyHV-2 Infection

by Jinwei Gao, Yiwen Hu, Min Xie, Hao Wu, Jiayu Wu, Bingwen Xi, Rui Song and Dongsheng Ou

Pathogens 2023, 12(11), 1329; https://doi.org/10.3390/pathogens12111329 - 8 Nov 2023

Viewed by 1674

Abstract

Cyprinid herpesvirus II (CyHV-2), a highly contagious pathogen of gibel carp (Carassius auratus gibelio), causes herpesviral hematopoietic necrosis disease (HVHND) and enormous financial losses. However, there is limited information available regarding the changes in plasma biochemical and immunological parameters and the response characteristics of Toll-like receptor 2 (TLR2) and Toll-like receptor 9 (TLR9) in gibel carp after CyHV-2 infection. To address this knowledge gap, a sub-lethal CyHV-2 infection was conducted in gibel carp, and the sample was collected daily from 1 to 7 days post infection. The plasma biochemical analyses showed significant decreases in the content of glucose, total cholesterol (TCHO), and total protein (TP), along with marked increases in the level of uric acid, urea, creatinine (CREA), Complement 3 (C3), immunoglobulin D (IgD), and immunoglobulin M (IgM) as well as in the activity of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in the infected group. Compared with the control group, the concentration of cortisol, triglyceride (TG), and Complement 4 (C4) had no noticeable alterations in the infected group. Real-time quantitative PCR analysis showed significant upregulation of TLR2 and TLR9 mRNA expression in the spleen, kidney, brain, liver, intestine, and gill post CyHV-2 infection. Interestingly, a time- and tissue-dependent expression profile has been comparatively observed for TLR2 and TLR9 in the above tissues of gibel carp after CyHV-2 infection, suggesting distinct roles between TLR2 and TLR9 in antiviral response to CyHV-2 infection. Overall, our results demonstrated that CyHV-2 infection led to the disruption of the physiological metabolic process and damage to the liver and kidney, and induced different spatiotemporal expression patterns of TLR2 and TLR9, ultimately stimulating antiviral response via innate and adaptive immune system. These findings may provide a deeper understanding of the host immunity response to CyHV-2 infection and offer novel perspectives for the prevention and treatment and therapeutic drug development against CyHV-2. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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Review

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19 pages, 1589 KiB

Open AccessReview

Pathogenic and Protective Roles of Neutrophils in Chlamydia trachomatis Infection

by Zoe E. R. Wilton, Andzoa N. Jamus, Susan B. Core and Kathryn M. Frietze

Pathogens 2025, 14(2), 112; https://doi.org/10.3390/pathogens14020112 - 23 Jan 2025

Viewed by 1206

Abstract

Chlamydia trachomatis (Ct) is an obligate intracellular pathogen that causes the most commonly diagnosed bacterial sexually transmitted infection (STI) and is a leading cause of preventable blindness globally. Ct infections can generate a strong pro-inflammatory immune response, leading to immune-mediated pathology in infected tissues. Neutrophils play an important role in mediating both pathology and protection during infection. Excessive neutrophil activation, migration, and survival are associated with host tissue damage during Chlamydia infections. In contrast, neutrophils also perform phagocytic killing of Chlamydia in the presence of IFN-γ and anti-Chlamydia antibodies. Neutrophil extracellular traps (NETs) and many neutrophil degranulation products have also demonstrated strong anti-Chlamydia functions. To counteract this neutrophil-mediated protection, Chlamydia has developed several evasion strategies. Various Chlamydia proteins can limit potentially protective neutrophil responses by directly targeting receptors present on the surface of neutrophils or neutrophil degranulation products. In this review, we provide a survey of current knowledge regarding the role of neutrophils in pathogenesis and protection, including the ways that Chlamydia circumvents neutrophil functions, and we propose critical areas for future research. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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19 pages, 1329 KiB

Open AccessReview

An Update on Anti-COVID-19 Vaccines and the Challenges to Protect Against New SARS-CoV-2 Variants

by Fábio Mambelli, Ana Carolina V. S. C. de Araujo, Jéssica P. Farias, Kivia Q. de Andrade, Luis C. S. Ferreira, Paola Minoprio, Luciana C. C. Leite and Sergio C. Oliveira

Pathogens 2025, 14(1), 23; https://doi.org/10.3390/pathogens14010023 - 1 Jan 2025

Cited by 2 | Viewed by 2323

Abstract

The COVID-19 pandemic has posed a significant threat to global health systems, with extensive impacts across many sectors of society. The pandemic has been responsible for millions of deaths worldwide since its first identification in late 2019. Several actions have been taken to prevent the disease, including the unprecedented fast development and global vaccination campaigns, which were pivotal in reducing symptoms and deaths. Given the impact of the pandemic, the continuous changes of the virus, and present vaccine technologies, this review analyzes how, so far, we have met the challenge posed by the emergence of new variants and discusses how next-generation pan-coronavirus vaccines, with enhanced longevity and breadth of immune responses, may be tackled with alternative administration routes and antigen delivery platforms. By addressing these critical aspects, this review aims to contribute to the ongoing efforts to achieve long-term control of COVID-19, stimulating the discussion and work on next-generation vaccines capable of facing future waves of infection. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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31 pages, 1716 KiB

Open AccessReview

Antiviral Activity of Zinc Finger Antiviral Protein (ZAP) in Different Virus Families

by Kívia Queiroz de Andrade and Claudio Cesar Cirne-Santos

Pathogens 2023, 12(12), 1461; https://doi.org/10.3390/pathogens12121461 - 17 Dec 2023

Cited by 9 | Viewed by 4351

Abstract

The CCCH-type zinc finger antiviral protein (ZAP) in humans, specifically isoforms ZAP-L and ZAP-S, is a crucial component of the cell’s intrinsic immune response. ZAP acts as a post-transcriptional RNA restriction factor, exhibiting its activity during infections caused by retroviruses and alphaviruses. Its function involves binding to CpG (cytosine-phosphate-guanine) dinucleotide sequences present in viral RNA, thereby directing it towards degradation. Since vertebrate cells have a suppressed frequency of CpG dinucleotides, ZAP is capable of distinguishing foreign genetic elements. The expression of ZAP leads to the reduction of viral replication and impedes the assembly of new virus particles. However, the specific mechanisms underlying these effects have yet to be fully understood. Several questions regarding ZAP’s mechanism of action remain unanswered, including the impact of CpG dinucleotide quantity on ZAP’s activity, whether this sequence is solely required for the binding between ZAP and viral RNA, and whether the recruitment of cofactors is dependent on cell type, among others. This review aims to integrate the findings from studies that elucidate ZAP’s antiviral role in various viral infections, discuss gaps that need to be filled through further studies, and shed light on new potential targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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15 pages, 1372 KiB

Open AccessReview

Immune Responses Potentially Involved in the Gestational Complications of Brucella Infection

by Lucía Zavattieri, Florencia Muñoz González, Mariana C. Ferrero and Pablo C. Baldi

Pathogens 2023, 12(12), 1450; https://doi.org/10.3390/pathogens12121450 - 14 Dec 2023

Cited by 4 | Viewed by 2704

Abstract

Infection by Brucella species in pregnant animals and humans is associated with an increased risk of abortion, preterm birth, and transmission of the infection to the offspring. The pathogen has a marked tropism for the placenta and the pregnant uterus and has the ability to invade and replicate within cells of the maternal–fetal unit, including trophoblasts and decidual cells. Placentitis is a common finding in infected pregnant animals. Several proinflammatory factors have been found to be increased in both the placenta of Brucella-infected animals and in trophoblasts or decidual cells infected in vitro. As normal pregnancies require an anti-inflammatory placental environment during most of the gestational period, Brucella-induced placentitis is thought to be associated with the obstetric complications of brucellosis. A few studies suggest that the blockade of proinflammatory factors may prevent abortion in these cases. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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17 pages, 2341 KiB

Open AccessReview

Current Understanding of Bacillus Calmette-Guérin-Mediated Trained Immunity and Its Perspectives for Controlling Intracellular Infections

by Ana Carolina V. S. C. de Araujo, Fábio Mambelli, Rodrigo O. Sanches, Fábio V. Marinho and Sergio C. Oliveira

Pathogens 2023, 12(12), 1386; https://doi.org/10.3390/pathogens12121386 - 24 Nov 2023

Cited by 6 | Viewed by 2566

Abstract

The bacillus Calmette–Guérin (BCG) is an attenuated bacterium derived from virulent Mycobacterium bovis. It is the only licensed vaccine used for preventing severe forms of tuberculosis in children. Besides its specific effects against tuberculosis, BCG administration is also associated with beneficial non-specific effects (NSEs) following heterologous stimuli in humans and mice. The NSEs from BCG could be related to both adaptive and innate immune responses. The latter is also known as trained immunity (TI), a recently described biological feature of innate cells that enables functional improvement based on metabolic and epigenetic reprogramming. Currently, the mechanisms related to BCG-mediated TI are the focus of intense research, but many gaps are still in need of elucidation. This review discusses the present understanding of TI induced by BCG, exploring signaling pathways that are crucial to a trained phenotype in hematopoietic stem cells and monocytes/macrophages lineage. It focuses on BCG-mediated TI mechanisms, including the metabolic-epigenetic axis and the inflammasome pathway in these cells against intracellular pathogens. Moreover, this study explores the TI in different immune cell types, its ability to protect against various intracellular infections, and the integration of trained innate memory with adaptive memory to shape next-generation vaccines. Full article

(This article belongs to the Special Issue Host Immune Responses to Intracellular Pathogens)

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