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A topical collection in Pathogens (ISSN 2076-0817). This collection belongs to the section "Immunological Responses and Immune Defense Mechanisms".

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Prof. Dr. Hinh Ly

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Department of Veterinary & Biomedical Sciences, University of Minnesota, Twin Cities, MN, USA
Interests: hemorrhagic fever viruses; arenaviruses; lassa fever; host-virus interactions; innate immunity; viral pathogenesis and host defense
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Dear Colleagues,

The "Immunological Responses and Immune Defense Mechanisms" section of Pathogens was established in 2019 with Professor Hinh Ly serving as its inaugural Section Editor-in-Chief. We are proud to have recruited 22 Editorial Board members and so far have published 26 papers in this section. Many original research papers and review articles on COVID-19 have recently been submitted to (and some have been published in) Pathogens with the hope that some of these published papers can help combat this deadly disease and/or curb the prolonged pandemic. Despite the ongoing pandemic, several areas of research in the general topic of immunological responses and immune defense mechanisms forge ahead. All areas of research, that include but are not necessarily limited to COVID-19, must therefore be highlighted in Pathogens. With this in mind, we are establishing this Topical Collection entitled "Immunological Responses and Immune Defense Mechanisms" to solicit primary research articles, reviews, editorials and commentaries on contemporary and hot topics from our esteemed editorial board members as well as from others for consideration of publication.

Prof. Dr. Hinh Ly
Collection Editor

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Published Papers (13 papers)

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2022

Jump to: 2021, 2020

13 pages, 1451 KiB

Open AccessArticle

Bendiocarb and Malathion Resistance in Two Major Malaria Vector Populations in Cameroon Is Associated with High Frequency of the G119S Mutation (Ace-1) and Overexpression of Detoxification Genes

by Idriss Nasser Ngangue-Siewe, Paulette Ndjeunia-Mbiakop, Nelly Armanda Kala-Chouakeu, Roland Bamou, Abdou Talipouo, Landre Djamouko-Djonkam, John Vontas, Konstantinos Mavridis, Jeannette Tombi, Timoléon Tchuinkam, Jean Arthur Mbida-Mbida and Christophe Antonio-Nkondjio

Pathogens 2022, 11(8), 824; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11080824 - 23 Jul 2022

Cited by 1 | Viewed by 1846

Abstract

The spread of pyrethroid resistance in malaria vectors is a major threat affecting the performance of current control measures. However, there is still not enough information on the resistance profile of mosquitoes to carbamates and organophosphates which could be used as alternatives. The present study assessed the resistance profile of Anopheles gambiae s.l. to bendiocarb and malathion, at the phenotypic and molecular levels, in different eco-epidemiological settings in Cameroon. Anopheles gambiae s.l. mosquitoes were collected from four eco-epidemiological settings across the country and their susceptibility level to bendiocarb and malathion was determined using WHO tubes bioassays. The ace-1 target site G119S mutation was screened by PCR. Reverse Transcription quantitative PCR 3-plex TaqMan assays were used to quantify the level of expression of eight genes associated with metabolic resistance. Resistance to malathion and/or bendiocarb was recorded in all study sites except in mosquitoes collected in Kaélé and Njombé. The Ace-1 (G119S) mutation was detected in high frequencies (>40%) in Kékem and Santchou. Both An. gambiae and An. coluzzii were detected carrying this mutation. The cytochrome P450s gene Cyp6p3 associated with carbamate resistance and the glutathione S-transferase gene Gste2 associated with organophosphate resistance were found to be overexpressed. Genes associated with pyrethroid (Cyp6m2, Cyp9k1, Cyp6p3) and organochlorine (Gste2, Cyp6z1, Cyp6m2) and cuticle resistance (Cyp4g16) were also overexpressed. The rapid spread of resistance to organophosphates and carbamates could seriously compromise future control strategies based on IRS. It is therefore becoming important to assess the magnitude of bendiocarb and malathion resistance countrywide. Full article

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2021

Jump to: 2022, 2020

25 pages, 11254 KiB

Open AccessArticle

High CD169 Monocyte/Lymphocyte Ratio Reflects Immunophenotype Disruption and Oxygen Need in COVID-19 Patients

by Antonella Minutolo, Vita Petrone, Marialaura Fanelli, Marco Iannetta, Martina Giudice, Ines Ait Belkacem, Marta Zordan, Pietro Vitale, Guido Rasi, Paola Sinibaldi-Vallebona, Loredana Sarmati, Massimo Andreoni, Fabrice Malergue, Emanuela Balestrieri, Sandro Grelli and Claudia Matteucci

Pathogens 2021, 10(12), 1639; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10121639 - 18 Dec 2021

Cited by 7 | Viewed by 3475

Abstract

Background: Sialoadhesin (CD169) has been found to be overexpressed in the blood of COVID-19 patients and identified as a biomarker in early disease. We analyzed CD169 in the blood cells of COVID-19 patients to assess its role as a predictive marker of disease progression and clinical outcomes. Methods: The ratio of the median fluorescence intensity of CD169 between monocytes and lymphocytes (CD169 RMFI) was analyzed by flow cytometry in blood samples of COVID-19 patients (COV) and healthy donors (HDs) and correlated with immunophenotyping, inflammatory markers, cytokine mRNA expression, pulmonary involvement, and disease progression. Results: CD169 RMFI was high in COV but not in HDs, and it correlated with CD8 T-cell senescence and exhaustion markers, as well as with B-cell maturation and differentiation in COV. CD169 RMFI correlated with blood cytokine mRNA levels, inflammatory markers, and pneumonia severity in patients who were untreated at sampling, and was associated with the respiratory outcome throughout hospitalization. Finally, we also report the first evidence of the specific ability of the spike protein of SARS-CoV-2 to trigger CD169 RMFI in a dose-dependent manner in parallel with IL-6 and IL-10 gene transcription in HD PBMCs stimulated in vitro. Conclusion: CD169 is induced by the spike protein and should be considered as an early biomarker for evaluating immune dysfunction and respiratory outcomes in COVID-19 patients. Full article

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14 pages, 2988 KiB

Open AccessArticle

Recombinant SARS-CoV-2 Nucleocapsid Protein: Expression, Purification, and Its Biochemical Characterization and Utility in Serological Assay Development to Assess Immunological Responses to SARS-CoV-2 Infection

by Da Di, Mythili Dileepan, Shamim Ahmed, Yuying Liang and Hinh Ly

Pathogens 2021, 10(8), 1039; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10081039 - 16 Aug 2021

Cited by 11 | Viewed by 3705

Abstract

The SARS-CoV-2 nucleocapsid protein (N) binds a single-stranded viral RNA genome to form a helical ribonucleoprotein complex that is packaged into virion particles. N is relatively conserved among coronaviruses and consists of the N-terminal domain (NTD) and C-terminal domain (CTD), which are flanked by three disorganized regions. N is highly immunogenic and has been widely used to develop a serological assay as a diagnostic tool for COVID-19 infection, although there is a concern that the natural propensity of N to associate with RNA might compromise the assay’s specificity. We expressed and purified from bacterial cells two recombinant forms of SARS-CoV-2 N, one from the soluble fraction of bacterial cell lysates that is strongly associated with bacterial RNAs and the other that is completely devoid of RNAs. We showed that both forms of N can be used to develop enzyme-linked immunosorbent assays (ELISAs) for the specific detection of human and mouse anti-N monoclonal antibodies (mAb) as well as feline SARS-CoV-2 seropositive serum samples, but that the RNA-free form of N exhibits a slightly higher level of sensitivity than the RNA-bound form to react to anti-N mouse mAb. Using the electrophoretic mobility shift assay (EMSA), we also showed that N preferentially binds ssRNA in a sequence-independent manner and that both NTD and CTD of N contribute to RNA-binding activity. Collectively, our study describes methods to express, purify, and biochemically characterize the SARS-CoV-2 N protein and to use it for the development of serological assays to detect SARS-CoV-2 infection. Full article

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34 pages, 19497 KiB

Open AccessArticle

The EBV-Encoded Oncoprotein, LMP1, Recruits and Transforms Fibroblasts via an ERK-MAPK-Dependent Mechanism

by Alexandra M Davis, Abigail Rapley, Christopher W Dawson, Lawrence S Young and Mhairi A Morris

Pathogens 2021, 10(8), 982; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10080982 - 03 Aug 2021

Cited by 7 | Viewed by 2832

Abstract

Latent membrane protein 1 (LMP1), the major oncoprotein encoded by Epstein–Barr virus (EBV), is expressed at widely variable levels in undifferentiated nasopharyngeal carcinoma (NPC) biopsies, fueling intense debate in the field as to the importance of this oncogenic protein in disease pathogenesis. LMP1-positive NPCs are reportedly more aggressive, and in a similar vein, the presence of cancer-associated fibroblasts (CAFs) surrounding “nests” of tumour cells in NPC serve as indicators of poor prognosis. However, there is currently no evidence linking LMP1 expression and the presence of CAFs in NPC. In this study, we demonstrate the ability of LMP1 to recruit fibroblasts in vitro in an ERK-MAPK-dependent mechanism, along with enhanced viability, invasiveness and transformation to a myofibroblast-like phenotype. Taken together, these findings support a putative role for LMP1 in recruiting CAFs to the tumour microenvironment in NPC, ultimately contributing to metastatic disease. Full article

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14 pages, 3260 KiB

Open AccessArticle

Synergistic Activation of Bovine CD4+ T Cells by Neutrophils and IL-12

by Zhengguo Xiao, Anmol Kandel and Lei Li

Pathogens 2021, 10(6), 694; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10060694 - 03 Jun 2021

Cited by 4 | Viewed by 2589

Abstract

CD4+ T cell activation requires inflammatory cytokines to provide a third signal (3SI), such as interleukin-12 (IL-12). We recently reported that bovine neutrophils can enhance the activation of bovine CD4+ T cells. To explore the interactions between neutrophils and third signal cytokines in bovine CD4+ T cell activation, naïve CD4+ T cells were isolated from cattle lymph nodes and stimulated for 3.5 days with anti-bovine CD3 (first signal; 1SI), anti-bovine CD28 (second signal; 2SI), and recombinant human IL-12 (3SI) in the presence or absence of neutrophils harvested from the same animals. Indeed, the strongest activation was achieved in the presence of all three signals, as demonstrated by CD25 upregulation, IFNγ production in CD4+ T cells, and secretion of IFNγ and IL-2 in cell supernatants. More importantly, 1SI plus neutrophils led to enhanced CD25 expression that was further increased by IL-12, suggesting synergistic action by IL-12 and neutrophils. Consistently, neutrophils significantly increased IFNγ production in 1SI plus IL-12-stimulated CD4+ T cells. Our data suggest the synergy of neutrophils and IL-12 as a novel regulator on bovine CD4+ T cell activation in addition to three signals. This knowledge could assist the development of immune interventions for the control of infectious diseases in cattle. Full article

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13 pages, 4072 KiB

Open AccessArticle

Role of Extracellular Mycobacteria in Blood-Retinal Barrier Invasion in a Zebrafish Model of Ocular TB

by Santhosh Kumar Damera, Ranjan Kumar Panigrahi, Sanchita Mitra and Soumyava Basu

Pathogens 2021, 10(3), 333; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10030333 - 13 Mar 2021

Cited by 6 | Viewed by 1860

Abstract

Intraocular inflammation following mycobacterial dissemination to the eye is common in tuberculosis (TB)-endemic countries. However, the early host–pathogen interactions during ocular dissemination are unknown. In this study, we investigated the early events during mycobacterial invasion of the blood-retinal barriers (BRBs) with fluorescent-tagged Mycobacterium marinum (Mm), host macrophages, and retinal vasculature in a zebrafish model of ocular TB. We found that Mm invaded the vascular endothelium in either the extracellular or intracellular (inside phagocytes) state, typically 3–4 days post-injection (dpi). Extracellular Mm are phagocytosed in the retinal tissue and progress to form a compact granuloma around 6 dpi. Intracellular Mm crossing the BRBs are likely to be less virulent and either persist inside solitary macrophages (in most cases) or progress to loosely arranged granuloma (rarely). The early interactions between mycobacteria and host immune cells can thus determine the course of disease during mycobacterial dissemination to the eye. Full article

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12 pages, 1932 KiB

Open AccessArticle

Development of a Recombinant Pichinde Virus-Vectored Vaccine against Turkey Arthritis Reovirus and Its Immunological Response Characterization in Vaccinated Animals

by Pawan Kumar, Tamer A. Sharafeldin, Rahul Kumar, Qinfeng Huang, Yuying Liang, Sagar M. Goyal, Robert E. Porter, Hinh Ly and Sunil K. Mor

Pathogens 2021, 10(2), 197; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10020197 - 13 Feb 2021

Cited by 7 | Viewed by 2243

Abstract

Vaccination may be an effective way to reduce turkey arthritis reovirus (TARV)-induced lameness in turkey flocks. However, there are currently no commercial vaccines available against TARV infection. Here, we describe the use of reverse genetics technology to generate a recombinant Pichinde virus (PICV) that expresses the Sigma C and/or Sigma B proteins of TARV as antigens. Nine recombinant PICV-based TARV vaccines were developed carrying the wild-type S1 (Sigma C) and/or S3 (Sigma B) genes from three different TARV strains. In addition, three recombinant PICV-based TARV vaccines were produced carrying codon-optimized S1 and/or S3 genes of a TARV strain. The S1 and S3 genes and antigens were found to be expressed in virus-infected cells via reverse transcriptase polymerase chain reaction (RT-PCR) and the direct fluorescent antibody (DFA) technique, respectively. Turkey poults inoculated with the recombinant PICV-based TARV vaccine expressing the bivalent TARV S1 and S3 antigens developed high anti-TARV antibody titers, indicating the immunogenicity (and safety) of this vaccine. Future in vivo challenge studies using a turkey reovirus infection model will determine the optimum dose and protective efficacy of this recombinant virus-vectored candidate vaccine. Full article

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32 pages, 2218 KiB

Open AccessReview

Role of Apoptotic Cell Clearance in Pneumonia and Inflammatory Lung Disease

by David Jiao Zheng, Maria Abou Taka and Bryan Heit

Pathogens 2021, 10(2), 134; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10020134 - 29 Jan 2021

Cited by 14 | Viewed by 7177

Abstract

Pneumonia and inflammatory diseases of the pulmonary system such as chronic obstructive pulmonary disease and asthma continue to cause significant morbidity and mortality globally. While the etiology of these diseases is highly different, they share a number of similarities in the underlying inflammatory processes driving disease pathology. Multiple recent studies have identified failures in efferocytosis—the phagocytic clearance of apoptotic cells—as a common driver of inflammation and tissue destruction in these diseases. Effective efferocytosis has been shown to be important for resolving inflammatory diseases of the lung and the subsequent restoration of normal lung function, while many pneumonia-causing pathogens manipulate the efferocytic system to enhance their growth and avoid immunity. Moreover, some treatments used to manage these patients, such as inhaled corticosteroids for chronic obstructive pulmonary disease and the prevalent use of statins for cardiovascular disease, have been found to beneficially alter efferocytic activity in these patients. In this review, we provide an overview of the efferocytic process and its role in the pathophysiology and resolution of pneumonia and other inflammatory diseases of the lungs, and discuss the utility of existing and emerging therapies for modulating efferocytosis as potential treatments for these diseases. Full article

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15 pages, 1119 KiB

Open AccessReview

The Roles of Inflammasomes in Host Defense against Mycobacterium tuberculosis

by Jialu Ma, Shasha Zhao, Xiao Gao, Rui Wang, Juan Liu, Xiangmei Zhou and Yang Zhou

Pathogens 2021, 10(2), 120; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10020120 - 25 Jan 2021

Cited by 10 | Viewed by 4022

Abstract

Mycobacterium tuberculosis (MTB) infection is characterized by granulomatous lung lesions and systemic inflammatory responses during active disease. Inflammasome activation is involved in regulation of inflammation. Inflammasomes are multiprotein complexes serving a platform for activation of caspase-1, which cleaves the proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 into their active forms. These cytokines play an essential role in MTB control. MTB infection triggers activation of the nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes in vitro, but only AIM2 and apoptosis-associated speck-like protein containing a caspase-activation recruitment domain (ASC), rather than NLRP3 or caspase-1, favor host survival and restriction of mycobacterial replication in vivo. Interferons (IFNs) inhibits MTB-induced inflammasome activation and IL-1 signaling. In this review, we focus on activation and regulation of the NLRP3 and AIM2 inflammasomes after exposure to MTB, as well as the effect of inflammasome activation on host defense against the infection. Full article

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2020

Jump to: 2022, 2021

21 pages, 297 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Dysregulated Humoral and Cellular Immunity by SARS-CoV-2

by Nima Taefehshokr, Sina Taefehshokr and Bryan Heit

Pathogens 2020, 9(12), 1027; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9121027 - 08 Dec 2020

Cited by 22 | Viewed by 4527

Abstract

The current coronavirus disease 2019 (COVID-19) pandemic, a disease caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), was first identified in December 2019 in China, and has led to thousands of mortalities globally each day. While the innate immune response serves as the first line of defense, viral clearance requires activation of adaptive immunity, which employs B and T cells to provide sanitizing immunity. SARS-CoV-2 has a potent arsenal of mechanisms used to counter this adaptive immune response through processes, such as T cells depletion and T cell exhaustion. These phenomena are most often observed in severe SARS-CoV-2 patients, pointing towards a link between T cell function and disease severity. Moreover, neutralizing antibody titers and memory B cell responses may be short lived in many SARS-CoV-2 patients, potentially exposing these patients to re-infection. In this review, we discuss our current understanding of B and T cells immune responses and activity in SARS-CoV-2 pathogenesis. Full article

12 pages, 2307 KiB

Open AccessEditor’s ChoiceArticle

The Surface Protein Fructose-1, 6 Bisphosphate Aldolase of Klebsiella pneumoniae Serotype K1: Role of Interaction with Neutrophils

by Chen-Hsiang Lee, Seng-Kee Chuah, Chia-Chi Chang and Fang-Ju Chen

Pathogens 2020, 9(12), 1009; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9121009 - 30 Nov 2020

Cited by 8 | Viewed by 2103

Abstract

Hypermucoviscosity phenotypic Klebsiella pneumoniae (HV-Kp) serotype K1 is the predominant pathogen of a pyogenic liver abscess, an emerging infectious disease that often complicates septic metastatic syndrome in diabetic patients with poor sugar control. HV-Kpisolates were more resistant to neutrophil phagocytosis than non-HV-Kpisolates because of different pathogen-associated molecular patterns. The protein expression of HV-Kp after interaction with neutrophils is unclear. We studied KP-M1 (HV phenotype; serotype K₁), DT-X (an acapsularmutant strain of KP-M1), and E. coli (ATCC 25922) with the model of Kp-infected neutrophils, using a comparative proteomic approach. One the identified protein, namely fructose-1, 6-bisphosphate aldolase (FBA), was found to be distributed in the KP-M1 after infecting neutrophils. Cell fractionation experiments showed that FBA is localized both to the cytoplasm and the outer membrane. Flow cytometry demonstrated that outer membrane-localized FBA was surface-accessible to FBA-specific antibody. The fba gene expression was enhanced in high glucose concentrations, which leads to increasing bacterial resistance to neutrophils phagocytosis and killing. The KP-M1 after FBA inhibitors and FBA-specific antibody treatment showed a significant reduction in bacterial resistance to neutrophils phagocytosis and killing, respectively, compared to KP-M1 without treatment. FBA is a highly conserved surface-exposed protein that is required for optimal interaction of HV-Kp to neutrophils. Full article

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25 pages, 1149 KiB

Open AccessEditor’s ChoiceReview

The Key Roles of Interferon Lambda in Human Molecular Defense against Respiratory Viral Infections

by Alexey A. Lozhkov, Sergey A. Klotchenko, Edward S. Ramsay, Herman D. Moshkoff, Dmitry A. Moshkoff, Andrey V. Vasin and Maria S. Salvato

Pathogens 2020, 9(12), 989; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9120989 - 26 Nov 2020

Cited by 18 | Viewed by 10198

Abstract

Interferons (IFN) are crucial for the innate immune response. Slightly more than two decades ago, a new type of IFN was discovered: the lambda IFN (type III IFN). Like other IFN, the type III IFN display antiviral activity against a wide variety of infections, they induce expression of antiviral, interferon-stimulated genes (MX1, OAS, IFITM1), and they have immuno-modulatory activities that shape adaptive immune responses. Unlike other IFN, the type III IFN signal through distinct receptors is limited to a few cell types, primarily mucosal epithelial cells. As a consequence of their greater and more durable production in nasal and respiratory tissues, they can determine the outcome of respiratory infections. This review is focused on the role of IFN-λ in the pathogenesis of respiratory viral infections, with influenza as a prime example. The influenza virus is a major public health problem, causing up to half a million lethal infections annually. Moreover, the virus has been the cause of four pandemics over the last century. Although IFN-λ are increasingly being tested in antiviral therapy, they can have a negative influence on epithelial tissue recovery and increase the risk of secondary bacterial infections. Therefore, IFN-λ expression deserves increased scrutiny as a key factor in the host immune response to infection. Full article

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5 pages, 519 KiB

Open AccessLetter

Increased Serum IgG4 Associates with Asthma and Tissue Eosinophilia in Chronic Rhinosinusitis Patients

by Mahnaz Ramezanpour, Hua Hu, Aden Lau, Sha Liu, April De Silva, Harrison Bolt, Karen Patterson, Maureen Rischmueller, Alkis J Psaltis, Peter-John Wormald, Susan Lester and Sarah Vreugde

Pathogens 2020, 9(10), 828; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9100828 - 10 Oct 2020

Cited by 2 | Viewed by 2107

Abstract

Chronic Rhinosinusitis (CRS) is a multifactorial disease where microorganisms’ innate and adaptive immunity can play a role. This study assessed the total IgG, IgG subclasses, IgE and IgA levels in serum samples from CRS and non-CRS control patients in relation to the disease severity, phenotype, histopathology and comorbidities. Total serum IgG, IgG1, IgG2, IgG3, IgG4 and IgE was determined from 10 non-CRS controls, 10 CRS without nasal polyp (CRSsNP) and 26 CRS with nasal polyp (CRSwNP) patients using ImmunoCap assays. Tissue lysates were analyzed for IgG levels by ELISA. Immunohistochemical analysis was used to measure the expression of IgE and IgG4 in tissue sections. The presence of anti-nuclear antigens (ANAs) against 12 autoantigens in sera and tissue lysates was determined by immunoblot assays. Total serum IgG/IgG1/IgG2 levels were higher in CRS patients vs. controls (p < 0.001), but were not different between CRSwNP and CRSsNP patients (p = 0.57). Serum IgG4/IgE levels were increased in CRSwNP patients compared to controls (p = 0.006), however, this relationship was attenuated by the inclusion of covariates. Serum IgG4 levels were more strongly associated with asthma (p = 0.038, exact median test) and tissue eosinophilia (Spearman’s rank rho = 0.51, p = 0.016) than IgE levels. No systemic ANAs were detected in any of the subjects tested. There was a polyclonal increase in serum immunoglobulins in CRS patients with elevated IgG4/IgE levels in CRSwNP patients having tissue eosinophilia and asthma. Full article

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Published Papers (13 papers)

2022

Jump to: 2021, 2020

2021

Jump to: 2022, 2020

2020

Jump to: 2022, 2021

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