The Other Side of the Coin: Anti-inflammatory Antibody Therapy for Infectious Diseases

ABSTRACT The inflammatory response to the fungus Pneumocystis jirovecii plays a central role in the respiratory failure associated with Pneumocystis pneumonia. To help ameliorate the inflammatory response, corticosteroids are used as an adjuvant to standard antimicrobial therapy. Corticosteroids, however, can have a wide range of effects (including deleterious effects) on the host immune response. To date, pathogen-specific antibody therapy has primarily been developed for both its direct antimicrobial activity (e.g., toxin and viral neutralization) and its ability to enhance the antimicrobial activity of the host immune response via effector cells, like macrophages and neutrophils. In this issue of Infection and Immunity, Hoy et al. (Z. Hoy, T. W. Wright, M. Elliott, J. Malone, et al., Infect Immun 88:e00640-19, 2020, https://doi.org/10.1128/IAI.00640-19) report on a surprising application of Pneumocystis-specific antibody therapy in treating disease by decreasing the inflammatory response. This effect appears to occur as a result of an enhanced phagocytic activity within the lung and an associated alteration in the macrophage phenotype. This study adds insight into our understanding of antibody activity and highlights the possibility of using antibody therapy to limit inflammation for other infectious diseases in which inflammatory damage plays a significant role in disease pathogenesis.

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Sepsis

10.1093/med/9780199568741.003.0309 ◽

2018 ◽

Author(s):

Graham Cooke

Keyword(s):

Immune Response ◽

Systemic Inflammatory Response Syndrome ◽

Inflammatory Response ◽

Primary Infection ◽

Clinical Manifestations ◽

Host Immune Response ◽

Organ Damage ◽

Clinical Syndrome ◽

Systemic Inflammatory Response ◽

Physiological Status

Sepsis is a clinical syndrome defined by the presence of both infection and a systemic inflammatory response with or without organ damage. The pathogenesis of sepsis is complex and may differ according to the infecting microbe, the site of primary infection, and the host’s immunological and physiological status prior to infection. The term ‘systemic inflammatory response syndrome’ refers to the clinical manifestations of a dysregulated host immune response, while ‘bacteraemia’, in contrast, refers to the presence of viable organisms that can be cultured from blood.

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B-Aggressive Lymphoma Gene (BAL) Is a Risk-Related, γIFN-Inducible Gene That Is Expressed in Primary Diffuse Large B-Cell Lymphomas with a Brisk Host Inflammatory Response.

Blood ◽

10.1182/blood.v104.11.2035.2035 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2035-2035

Author(s):

Przemyslaw Juszczynski ◽

Jeffery L. Kutok ◽

Ricardo C.T. Aguiar ◽

Joydeep Mitra ◽

Margaret A. Shipp

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

B Cell ◽

Binding Site ◽

B Cell Lymphoma ◽

Host Immune Response ◽

Aggressive Lymphoma ◽

Current Therapy ◽

Host Inflammatory Response ◽

Large B Cell

Abstract Although diffuse large B-cell lymphoma (DLBCL) is potentially curable with current therapy, a significant number of DLBCL patients still die of their disease. In a broad-based screen for genes and pathways associated with poor DLBCL outcome, we previously identified a novel risk-related gene, termed BAL (B-aggressive lymphoma). Thereafter, we cloned and characterized a major BAL partner protein, BBAP (B-aggressive lymphoma and BAL binding partner), described the nuclear trafficking patterns of both proteins and demonstrated that BAL functions as a modulator of transcription. In the current study, we characterized BAL expression in normal tonsil and primary DLBCLs and defined BAL regulation and potential functions in both cell types. Immunohistochemical staining of normal tonsil revealed that BAL was expressed by small numbers of germinal center (GC) cells and interfollicular cells with the morphologic features of centroblasts (with the GC) and immunoblasts (within the interfollicular areas). In primary DLBCLs, BAL was expressed by the malignant B cells. To gain insights regarding the regulation of BAL and BBAP expression in DLBCLs, we analyzed a series of 176 primary tumor biopsies transcriptionally profiled an U133A/B Affymetrix microarrays. BAL/BBAP high-expressing DLBCLs had evidence of a brisk host immune response, including increased expression of T/NK-cell receptor and activation pathway components, complement cascade members, macrophage/dendritic cells markers and γIFN-induced transcripts, raising the possibility that BAL was induced by γIFN. Consistent with this hypothesis, γIFN treatment of DLBCL cell lines with low basal levels of BAL markedly increased BAL expression. In silico analysis revealed that the BAL and BBAP genes are located in 3q21 in head-to-head orientation and share the same CpG-related promoter. This shared promoter contains a conserved γIFN-responsive module composed of IRF and STAT binding elements. The BAL/BBAP bidirectional promoter was cloned into a pGL3 luciferase promoterless reporter vector and found to increase luciferase activity > 20-fold following γIFN stimulation. To gain further insights into regulation of BAL transcription, mutant versions of BAL promoter were generated and cloned. Luciferase assays demonstrated that the IRF binding site was necessary for γIFN-induced BAL transcription, whereas the STAT1 binding site had an accessory role. Taken together, these results demonstrate that BAL and BBAP genes are transcriptionally activated by γIFN in DLBCLs with features of a brisk host immune response including γIFN signaling. Preliminary studies suggest that BAL limits the efficacy of the observed host inflammatory response.

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Interplay Among the Oral Microbiome, Oral Cavity Conditions, the Host Immune Response, Diabetes Mellitus, and Its Associated-Risk Factors—An Overview

Frontiers in Oral Health ◽

10.3389/froh.2021.697428 ◽

2021 ◽

Vol 2 ◽

Author(s):

Thais de Cássia Negrini ◽

Iracilda Zeppone Carlos ◽

Cristiane Duque ◽

Karina Sampaio Caiaffa ◽

Rodrigo Alex Arthur

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Immune Response ◽

Oral Health ◽

Inflammatory Response ◽

Oral Cavity ◽

Periodontal Disease ◽

Host Immune Response ◽

Oral Microbiome ◽

Associated Risk Factors

This comprehensive review of the literature aimed to investigate the interplay between the oral microbiome, oral cavity conditions, and host immune response in Diabetes mellitus (DM). Moreover, this review also aimed to investigate how DM related risk factors, such as advanced age, hyperglycemia, hyperlipidemia, obesity, hypertension and polycystic ovary syndrome (PCOS), act in promoting or modifying specific mechanisms that could potentially perpetuate both altered systemic and oral conditions. We found that poorly controlled glycemic index may exert a negative effect on the immune system of affected individuals, leading to a deficient immune response or to an exacerbation of the inflammatory response exacerbating DM-related complications. Hyperglycemia induces alterations in the oral microbiome since poor glycemic control is associated with increased levels and frequencies of periodontal pathogens in the subgingival biofilm of individuals with DM. A bidirectional relationship between periodontal diseases and DM has been suggested: DM patients may have an exaggerated inflammatory response, poor repair and bone resorption that aggravates periodontal disease whereas the increased levels of systemic pro-inflammatory mediators found in individuals affected with periodontal disease exacerbates insulin resistance. SARS-CoV-2 infection may represent an aggravating factor for individuals with DM. Individuals with DM tend to have low salivary flow and a high prevalence of xerostomia, but the association between prevalence/experience of dental caries and DM is still unclear. DM has also been associated to the development of lesions in the oral mucosa, especially potentially malignant ones and those associated with fungal infections. Obesity plays an important role in the induction and progression of DM. Co-affected obese and DM individuals tend to present worse oral health conditions. A decrease in HDL and, an increase in triglycerides bloodstream levels seem to be associated with an increase on the load of periodontopathogens on oral cavity. Moreover, DM may increase the likelihood of halitosis. Prevalence of impaired taste perception and impaired smell recognition tend to be greater in DM patients. An important interplay among oral cavity microbiome, DM, obesity and hypertension has been proposed as the reduction of nitrate into nitrite, in addition to contribute to lowering of blood pressure, reduces oxidative stress and increases insulin secretion, being these effects desirable for the control of obesity and DM. Women with PCOS tend to present a distinct oral microbial composition and an elevated systemic response to selective members of this microbial community, but the association between oral microbiome, PCOS are DM is still unknown. The results of the studies presented in this review suggest the interplay among the oral microbiome, oral cavity conditions, host immune response and DM and some of the DM associated risk factors exist. DM individuals need to be encouraged and motivated for an adequate oral health care. In addition, these results show the importance of adopting multidisciplinary management of DM and of strengthening physicians-dentists relationship focusing on both systemic and on oral cavity conditions of DM patients.

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Detection of Antibody Responses Against SARS-CoV-2 in Plasma and Saliva From Vaccinated and Infected Individuals

Frontiers in Immunology ◽

10.3389/fimmu.2021.759688 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jéromine Klingler ◽

Gregory S. Lambert ◽

Vincenza Itri ◽

Sean Liu ◽

Juan C. Bandres ◽

...

Keyword(s):

Immune Response ◽

Specific Antibody ◽

Strong Correlation ◽

Respiratory Virus ◽

Host Immune Response ◽

Antibody Responses ◽

Lower Prevalence ◽

Antiviral Activities ◽

Virus Exposure ◽

Complement Deposition

Antibodies (Abs) are essential for the host immune response against SARS-CoV-2, and all the vaccines developed so far have been designed to induce Abs targeting the SARS-CoV-2 spike. Many studies have examined Ab responses in the blood from vaccinated and infected individuals. However, since SARS-CoV-2 is a respiratory virus, it is also critical to understand the mucosal Ab responses at the sites of initial virus exposure. Here, we examined plasma versus saliva Ab responses in vaccinated and convalescent patients. Although saliva levels were significantly lower, a strong correlation was observed between plasma and saliva total Ig levels against all SARS-CoV-2 antigens tested. Virus-specific IgG1 responses predominated in both saliva and plasma, while a lower prevalence of IgM and IgA1 Abs was observed in saliva. Antiviral activities of plasma Abs were also studied. Neutralization titers against the initial WA1 (D614G), B.1.1.7 (alpha) and B.1.617.2 (delta) strains were similar but lower against the B.1.351 (beta) strain. Spike-specific antibody-dependent cellular phagocytosis (ADCP) activities were also detected and the levels correlated with spike-binding Ig titers. Interestingly, while neutralization and ADCP potencies of vaccinated and convalescent groups were comparable, enhanced complement deposition to spike-specific Abs was noted in vaccinated versus convalescent groups and corresponded with higher levels of IgG1 plus IgG3 among the vaccinated individuals. Altogether, this study demonstrates the detection of Ab responses after vaccination or infection in plasma and saliva that correlate significantly, although Ig isotypic differences were noted. The induced plasma Abs displayed Fab-mediated and Fc-dependent functions with comparable neutralization and ADCP potencies, but a greater capacity to activate complement was elicited upon vaccination.

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SARS-CoV-2: From Structure to Pathology, Host Immune Response and Therapeutic Management

Microorganisms ◽

10.3390/microorganisms8101468 ◽

2020 ◽

Vol 8 (10) ◽

pp. 1468

Author(s):

Grigore Mihaescu ◽

Mariana Carmen Chifiriuc ◽

Ciprian Iliescu ◽

Corneliu Ovidiu Vrancianu ◽

Lia-Mara Ditu ◽

...

Keyword(s):

Immune Response ◽

Molecular Mechanisms ◽

Prolonged Exposure ◽

Vaccine Development ◽

Host Immune Response ◽

Physical Factors ◽

Respiratory Pathogens ◽

Inflammatory Conditions ◽

Multiplication Cycle ◽

Wide Range

Coronaviruses are large, enveloped viruses with a single-stranded RNA genome, infecting both humans and a wide range of wild and domestic animals. SARS-CoV-2, the agent of the COVID-19 pandemic, has 80% sequence homology with SARS-CoV-1 and 96–98% homology with coronaviruses isolated from bats. The spread of infection is favored by prolonged exposure to high densities of aerosols indoors. Current studies have shown that SARS-CoV-2 is much more stable than other coronaviruses and viral respiratory pathogens. The severe forms of infection are associated with several risk factors, including advanced age, metabolic syndrome, diabetes, obesity, chronic inflammatory or autoimmune disease, and other preexisting infectious diseases, all having in common the pre-existence of a pro-inflammatory condition. Consequently, it is essential to understand the relationship between the inflammatory process and the specific immune response in SARS-CoV-2 infection. In this review, we present a general characterization of the SARS-CoV-2 virus (origin, sensitivity to chemical and physical factors, multiplication cycle, genetic variability), the molecular mechanisms of COVID-19 pathology, the host immune response and discuss how the inflammatory conditions associated with different diseases could increase the risk of COVID-19. Last, but not least, we briefly review the SARS-CoV-2 diagnostics, pharmacology, and future approaches toward vaccine development.

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Understanding the immune responses involved in mediating protection or immunopathology during leishmaniasis

Biochemical Society Transactions ◽

10.1042/bst20200606 ◽

2021 ◽

Author(s):

Thalia Pacheco-Fernandez ◽

Greta Volpedo ◽

Chaitenya Verma ◽

Abhay R. Satoskar

Keyword(s):

Immune Response ◽

Immune Responses ◽

Public Health Problem ◽

Host Immune Response ◽

Sand Fly ◽

Leishmania Infection ◽

Major Public Health Problem ◽

Wide Range ◽

Vector Borne ◽

Leishmania Parasites

Leishmaniasis is a vector-borne Neglected Tropical Disease (NTD) transmitted by the sand fly and is a major public health problem worldwide. Infections caused by Leishmania clinically manifest as a wide range of diseases, such as cutaneous (CL), diffuse cutaneous (DCL), mucosal (MCL) and visceral leishmaniasis (VL). The host innate and adaptative immune responses play critical roles in the defense against leishmaniasis. However, Leishmania parasites also manipulate the host immune response for their survival and replication. In addition, other factors such as sand fly salivary proteins and microbiota also promote disease susceptibility and parasite spread by modulating local immune response. Thus, a complex interplay between parasite, sand fly and the host immunity governs disease severity and outcome. In this review, we discuss the host immune response during Leishmania infection and highlight the factors associated with resistance or susceptibility.

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Quarterly picks from the editors

Science Translational Medicine ◽

10.1126/scitranslmed.abg0485 ◽

2020 ◽

Vol 12 (574) ◽

pp. eabg0485

Keyword(s):

Immune Response ◽

T Cell ◽

Infectious Diseases ◽

Translational Medicine ◽

Host Immune Response ◽

Cell Engineering ◽

Intestinal Microbiome ◽

Car T Cell ◽

Car T ◽

T Cell Engineering

Four times a year, the Science Translational Medicine editors select recently published articles across the Science family of journals and highlight interesting translational ties. These short write-ups identify common links between disparate diseases; technologies and research approaches that could prove complementary; and biomedical insights that may inform therapies or treatments. This quarter’s articles cover flexible biosensors, SARS-CoV-2 transmission from a genomics perspective, advances in CAR T cell engineering, the intestinal microbiome, the host immune response to SARS-CoV-2, and strategies for treating infectious diseases.

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Steryl Glycosides in Fungal Pathogenesis: An Understudied Immunomodulatory Adjuvant

Journal of Fungi ◽

10.3390/jof6010025 ◽

2020 ◽

Vol 6 (1) ◽

pp. 25 ◽

Cited By ~ 2

Author(s):

Tyler G. Normile ◽

Kyle McEvoy ◽

Maurizio Del Poeta

Keyword(s):

Immune Response ◽

Fungal Infections ◽

Treatment Options ◽

Host Immune Response ◽

Novel Treatment ◽

Wide Range ◽

Efficacious Vaccine ◽

Lipid Compounds ◽

Fungal Interactions

Invasive fungal infections pose an increasing threat to human hosts, especially in immunocompromised individuals. In response to the increasing morbidity and mortality of fungal infections, numerous groups have shown great strides in uncovering novel treatment options and potential efficacious vaccine candidates for this increasing threat due to the increase in current antifungal resistance. Steryl glycosides are lipid compounds produced by a wide range of organisms, and are largely understudied in the field of pathogenicity, especially to fungal infections. Published works over the years have shown these compounds positively modulating the host immune response. Recent advances, most notably from our lab, have strongly indicated that steryl glycosides have high efficacy in protecting the host against lethal Cryptococcal infection through acting as an immunoadjuvant. This review will summarize the keystone studies on the role of steryl glycosides in the host immune response, as well as elucidate the remaining unknown characteristics and future perspectives of these compounds for the host–fungal interactions.

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