A Common Food Glycan, Pectin, Shares an Antigen with Streptococcus pneumoniae Capsule

ABSTRACT We are exposed daily to many glycans from bacteria and food plants. Bacterial glycans are generally antigenic and elicit antibody responses. It is unclear if food glycans’ sharing of antigens with bacterial glycans influences our immune responses to bacteria. We studied 14 different plant foods for cross-reactivity with monoclonal antibodies (MAbs) against 24 pneumococcal serotypes which commonly cause infections and are included in pneumococcal vaccines. Serotype 15B-specific MAb cross-reacts with fruit peels, and serotype 10A MAb cross-reacts with many natural and processed plant foods. The serotype 10A cross-reactive epitope is 1,6-β-galactosidase [βGal(1-6)], present in the rhamno-galacturonan I (RG-I) domain of pectin. Despite wide consumption of pectin, the immune response to 10A is comparable to the responses to other serotypes. An antipectin antibody can opsonize serotype 10A pneumococci, and the shared βGal(1-6) may be useful as a simple vaccine against 10A. Impact of food glycans should be considered in host-pathogen interactions and future vaccine designs. IMPORTANCE The impact of food consumption on vaccine responses is unknown. Streptococcus pneumoniae (the pneumococcus) is an important human pathogen, and its polysaccharide capsule is used as a vaccine. We show that capsule type 10A in a pneumococcal vaccine shares an antigenic epitope, βGal(1-6), with pectin, which is in many plant foods and is widely consumed. Immune response to 10A is comparable to that seen with other capsule types, and pectin ingestion may have little impact on vaccine responses. However, antibody to pectin can kill serotype 10A pneumococci and this shared epitope may be considered in pneumococcal vaccine designs.

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Impact of Influenza on Pneumococcal Vaccine Effectiveness during Streptococcus pneumoniae Infection in Aged Murine Lung

Vaccines ◽

10.3390/vaccines8020298 ◽

2020 ◽

Vol 8 (2) ◽

pp. 298

Author(s):

Ermias Jirru ◽

Stefi Lee ◽

Rebecca Harris ◽

Jianjun Yang ◽

Soo Jung Cho ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Immune Responses ◽

Pneumococcal Vaccine ◽

Influenza A ◽

Secondary Infection ◽

Influenza Infection ◽

Vaccine Effectiveness ◽

Murine Lung ◽

Vaccine Responses ◽

Secondary Infections

Changes in innate and adaptive immune responses caused by viral imprinting can have a significant direct or indirect influence on secondary infections and vaccine responses. The purpose of our current study was to investigate the role of immune imprinting by influenza on pneumococcal vaccine effectiveness during Streptococcus pneumoniae infection in the aged murine lung. Aged adult (18 months) mice were vaccinated with the pneumococcal polyvalent vaccine Pneumovax (5 mg/mouse). Fourteen days post vaccination, mice were instilled with PBS or influenza A/PR8/34 virus (3.5 × 102 PFU). Control and influenza-infected mice were instilled with PBS or S. pneumoniae (1 × 103 CFU, ATCC 6303) on day 7 of infection and antibacterial immune responses were assessed in the lung. Our results illustrate that, in response to a primary influenza infection, there was diminished bacterial clearance and heightened production of pro-inflammatory cytokines, such as IL6 and IL1β. Vaccination with Pneumovax decreased pro-inflammatory cytokine production by modulating NFҡB expression; however, these responses were significantly diminished after influenza infection. Taken together, the data in our current study illustrate that immune imprinting by influenza diminishes pneumococcal vaccine efficacy and, thereby, may contribute to increased susceptibility of older persons to a secondary infection with S. pneumoniae.

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Conjugation of PspA4Pro with Capsular Streptococcus pneumoniae Polysaccharide Serotype 14 Does Not Reduce the Induction of Cross-Reactive Antibodies

Clinical and Vaccine Immunology ◽

10.1128/cvi.00118-17 ◽

2017 ◽

Vol 24 (8) ◽

Cited By ~ 6

Author(s):

Míriam A. da Silva ◽

Thiago R. Converso ◽

Viviane M. Gonçalves ◽

Luciana C. C. Leite ◽

Martha M. Tanizaki ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Capsular Polysaccharide ◽

Vaccine Coverage ◽

Protein A ◽

Surface Protein ◽

Cross Reactivity ◽

Carrier Protein ◽

Content Type ◽

Clade 1 ◽

The Impact

ABSTRACT Current pneumococcal vaccines are composed of bacterial polysaccharides as antigens, plain or conjugated to carrier proteins. While efficacious against vaccine serotypes, epidemiologic data show an increasing incidence of infections caused by nonvaccine serotypes of Streptococcus pneumoniae. The use of pneumococcal surface protein A (PspA) as a carrier protein in a conjugate vaccine could help prevent serotype replacement by increasing vaccine coverage and reducing selective pressure of S. pneumoniae serotypes. PspA is present in all pneumococcal strains, is highly immunogenic, and is known to induce protective antibodies. Based on its sequence, PspA has been classified into three families and six clades. A PspA fragment derived from family 2, clade 4 (PspA4Pro), was shown to generate antibodies with a broad range of cross-reactivity, across clades and families. Here, PspA4Pro was modified and conjugated to capsular polysaccharide serotype 14 (PS14). We investigated the impact of conjugation on the immune response induced to PspA4Pro and PS14. Mice immunized with the PS14-mPspA4Pro conjugate produced higher titers of anti-PS14 antibodies than the animals that received coadministered antigens. The conjugate induced antibodies with opsonophagocytic activity against PS14-carrying strains, as well as against a panel of strains bearing PspAs from five clades (encompassing families 1 and 2) bearing a non-PS14 serotype. Furthermore, mice immunized with PS14-mPspA4Pro were protected against nasal colonization with a nonrelated S. pneumoniae strain bearing PspA from clade 1, serotype 6B. These results demonstrate that the cross-reactivity mediated by PspA4Pro is retained following conjugation, supporting the use of PspA4 as a carrier protein in order to enhance pneumococcal vaccine coverage and encourage its further investigation as a candidate in future vaccine designs.

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Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses

Vaccines ◽

10.3390/vaccines9060629 ◽

2021 ◽

Vol 9 (6) ◽

pp. 629

Author(s):

Megan M. Dunagan ◽

Kala Hardy ◽

Toru Takimoto

Keyword(s):

Immune Response ◽

Immune Responses ◽

Influenza A Virus ◽

Influenza A ◽

Human Populations ◽

Lymphocyte Migration ◽

Host Immune Responses ◽

Mhc Molecules ◽

The Impact

Influenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and NS1, which antagonize the host innate immune response. By transcriptomic analysis, we previously showed that PA-X is a major contributor for general shutoff, while shutoff active NS1 specifically inhibits the expression of host cytokines, MHC molecules, and genes involved in innate immunity in cultured human cells. So far, the impact of these shutoff proteins in the acquired immune response in vivo has not been determined in detail. In this study, we analyzed the effects of PA-X and NS1 shutoff activities on immune response using recombinant influenza A/California/04/2009 viruses containing mutations affecting the expression of shutoff active PA-X and NS1 in a mouse model. Our data indicate that the virus without shutoff activities induced the strongest T and B cell responses. Both PA-X and NS1 reduced host immune responses, but shutoff active NS1 most effectively suppressed lymphocyte migration to the lungs, antibody production, and the generation of IAV specific CD4+ and CD8+ T cells. NS1 also prevented the generation of protective immunity against a heterologous virus challenge. These data indicate that shutoff active NS1 plays a major role in suppressing host immune responses against IAV infection.

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Dairy Heifers Naturally Exposed toFasciola hepaticaDevelop a Type 2 Immune Response and Concomitant Suppression of Leukocyte Proliferation

Infection and Immunity ◽

10.1128/iai.00607-17 ◽

2017 ◽

Vol 86 (1) ◽

Cited By ~ 3

Author(s):

John Graham-Brown ◽

Catherine Hartley ◽

Helen Clough ◽

Aras Kadioglu ◽

Matthew Baylis ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Peripheral Blood ◽

Serum Antibody ◽

Enzyme Linked Immunosorbent Assay ◽

Mixed Effect ◽

Content Type ◽

Grazing Season ◽

Type 2 Immune Response

ABSTRACTFasciola hepaticais a parasitic trematode of global importance in livestock. Control strategies reliant on anthelmintics are unsustainable due to the emergence of drug resistance. Vaccines are under development, but efficacies are variable. Evidence from experimental infection suggests that vaccine efficacy may be affected by parasite-induced immunomodulation. Little is known about the immune response toF. hepaticafollowing natural exposure. Hence, we analyzed the immune responses over time in calves naturally exposed toF. hepaticainfection. Cohorts of replacement dairy heifer calves (n= 42) with no prior exposure toF. hepatica, on three commercial dairy farms, were sampled over the course of a grazing season. Exposure was determined through anF. hepatica-specific serum antibody enzyme-linked immunosorbent assay (ELISA) and fluke egg counts. Concurrent changes in peripheral blood leukocyte subpopulations, lymphocyte proliferation, and cytokine responses were measured. Relationships between fluke infection and immune responses were analyzed by using multivariable linear mixed-effect models. All calves from one farm showed evidence of exposure, while cohorts from the remaining two farms remained negative over the grazing season. A type 2 immune response was associated with exposure, with increased interleukin-4 (IL-4) production, IL-5 transcription, and eosinophilia. Suppression of parasite-specific peripheral blood mononuclear cell (PBMC) proliferation was evident, while decreased mitogen-stimulated gamma interferon (IFN-γ) production suggested immunomodulation, which was not restricted to parasite-specific responses. Our findings show that the global immune response is modulated toward a nonproliferative type 2 state following natural challenge withF. hepatica. This has implications in terms of the timing of the administration of vaccination programs and for host susceptibility to coinfecting pathogens.

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Clearance of Staphylococcus aureus Nasal Carriage Is T Cell Dependent and Mediated through Interleukin-17A Expression and Neutrophil Influx

Infection and Immunity ◽

10.1128/iai.00084-13 ◽

2013 ◽

Vol 81 (6) ◽

pp. 2070-2075 ◽

Cited By ~ 63

Author(s):

Nathan K. Archer ◽

Janette M. Harro ◽

Mark E. Shirtliff

Keyword(s):

Staphylococcus Aureus ◽

Immune Response ◽

T Cell ◽

Immune Responses ◽

Neutrophil Migration ◽

Nasal Carriage ◽

Causal Connection ◽

Content Type ◽

Neutrophil Influx ◽

Increased Risk

ABSTRACTThe anterior nares of humans are the major reservoir forStaphylococcus aureuscolonization. Approximately 20% of the healthy human population is persistently and 80% is intermittently colonized withS. aureusin the nasal cavity. Previous studies have shown a strong causal connection betweenS. aureusnasal carriage and increased risk of nosocomial infection, as well as increased carriage due to immune dysfunction. However, the immune responses that permit persistence or mediate clearance ofS. aureuson the nasal mucosa are fundamentally undefined. In this study, we developed a carriage model in C57BL/6J mice and showed that clearance begins 14 days postinoculation. In contrast, SCID mice that have a deficient adaptive immune response are unable to eliminateS. aureuseven after 28 days postinoculation. Furthermore, decolonization was found to be T cell mediated but B cell independent by evaluating carriage clearance in T-cell receptor β/δ (TCR-β/δ) knockout (KO) and IgH-μ KO mice, respectively. Upregulation of the cytokines interleukin 1β (IL-1β), KC (also termed CXC ligand 1 [CXCL1]), and IL-17A occurred following inoculation with intranasalS. aureus. IL-17A production was crucial for clearance, since IL-17A-deficient mice were unable to effectively eliminateS. aureuscarriage. Subsequently, cell differential counts were evaluated from nasal lavage fluid obtained from wild-type and IL-17A-deficient colonized mice. These counts displayed IL-17A-dependent neutrophil migration. Antibody-mediated depletion of neutrophils in colonized mice caused reduced clearance compared to that in isotype-treated controls. Our data suggest that the Th17-associated immune response is required for nasal decolonization. This response is T cell dependent and mediated via IL-17A production and neutrophil influx. Th17-associated immune responses may be targeted for strategies to mitigate distal infections originating from persistentS. aureuscarriage in humans.

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Genetic polymorphisms mediating behavioural and immune response to pathogens may moderate the impact of the COVID-19 pandemic: a pilot study

10.1101/2020.06.03.20120998 ◽

2020 ◽

Author(s):

Ravi Philip Rajkumar

Keyword(s):

Immune Response ◽

Pilot Study ◽

Immune Responses ◽

Genetic Variants ◽

Mortality Rates ◽

Therapeutic Strategies ◽

Published Data ◽

Entire World ◽

S Allele ◽

The Impact

AbstractBackgroundThe COVID-19 pandemic has affected the entire world, but there are wide variations in prevalence and mortality across nations. Genetic variants which influence behavioural or immune responses to pathogens, selected for by pathogen pressure, may influence this variability. Two relevant polymorphisms in this context are the s allele of the serotonin transporter promoter (5-HTTLPR) and the G allele of the interleukin-6 gene (IL-6 rs1800795).MethodsThe frequencies of the 5-HTTLPR s allele and IL-6 rs1800795 G allele were obtained from published data. The correlations between these allele frequencies and the prevalence and mortality rates of COVID-19 were examined across 44 nations.ResultsThe IL-6 rs1800795 G allele was negatively correlated with COVID-19 prevalence (ρ = −0.466, p < 0.01) and mortality (ρ = −0.591, p<0.001) across nations. The 5-HTTLPR s allele was negatively correlated with COVID-19 mortality rates (ρ = −0.437, p = 0.023).ConclusionsThese results suggest that a significant relationship exists between genetic variants that influence behavioural and immune responses to pathogens and indices of the impact of COVID-19 across nations. Further investigation of these variants and their correlates may permit the development of better preventive or therapeutic strategies in the management of the COVID-19 pandemic.

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P02.03 Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.39 ◽

2020 ◽

Vol 8 (Suppl 2) ◽

pp. A21.1-A21

Author(s):

E Staib ◽

K Leuchte ◽

M Thelen ◽

P Gödel ◽

A Lechner ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Thermal Ablation ◽

Microwave Ablation ◽

T Cell Response ◽

Tumor Control ◽

Free Survival ◽

Interleukin 5 ◽

The Impact

BackgroundThermal ablative therapies, such as microwave ablation (MWA) or radiofrequency ablation (RFA), are standard treatments for HCC. In addition to the local tumor destruction, abscopal effects (a reduction of a tumor mass in areas that were not included in the thermal ablation) could be observed. These systemic effects may be mediated by anti-tumor immune response, which has been described for RFA. MWA is rapidly replacing RFA, but systemic immunostimulatory effects of MWA treatment have been poorly studied.Materials and MethodsPatients receiving MWA for localized HCC were included in this study. Effects of MWA on peripheral blood mononuclear cells (PBMC) of HCC patients treated with MWA were analyzed by multicolor flow cytometry. Tumor-specific immune responses against 7 shared tumor antigens were analyzed using peptide pools in 3-color Fluorospot assays (Interferon-y/Interleukin-5/Interleukin-10). The impact of type, density and localization of tumor-infiltrating lymphocytes was assessed by immunohistochemistry (IHC) of CD3, CD4, CD8, FoxP3, CD38 and CD20 and digital image analyses (Immunoscore) of tumor specimens in an additional cohort of patients who received combined surgical resection and thermal ablation.ResultsWhile comprehensive flow cytometric analyses in sequential samples (day 0, 7 and 90) of a prospective patient cohort (n=23) demonstrated only moderate effects of MWA on circulating immune cell subsets, Fluorospot analyses revealed de novo or enhanced tumor-specific immune responses in 30% of these patients. This anti-tumor immune response was related to tumor control. Interferon-y and Interleukin-5 T cell responses against cancer testis antigens were more frequent in patients with a long-time remission (>12 months) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients). Presence of tumor-specific T cell response (Interferon-y and/or Interleukin-5) was associated to longer progression-free survival (15.0 vs. 10.0 months). Immunohistochemical analyses of resected tumor samples revealed that a high T cell infiltration in a second tumor lesion at the time of thermal ablation was associated with superior disease-free survival (37.4 vs. 13.1 months).ConclusionsOur data demonstrates remarkable immune-related effects of MWA in HCC patients. This study and provides additional evidence for a combination of thermal ablation and immunotherapy in this challenging disease.Funding‘Koeln Fortune’ and ‘CAP-CMMC’ local research grant (to P.G. and H.A.S.) supported our research.Disclosure InformationE. Staib: None. K. Leuchte: None. M. Thelen: None. P. Gödel: None. A. Lechner: None. P. Zentis: None. M. Garcia-Marquez: None. D. Waldschmidt: None. R.R. Datta: None. R. Wahba: None. C. Wybranski: None. T. Zander: None. A. Quaas: None. U. Drebber: None. D.L. Stippel: None. C. Bruns: None. K. Wennhold: None. M. von Bergwelt-Baildon: None. H.A. Schlösser: None.

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Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniaeCoinfection

mBio ◽

10.1128/mbio.01335-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 4

Author(s):

Sean Roberts ◽

Sharon L. Salmon ◽

Donald J. Steiner ◽

Clare M. Williams ◽

Dennis W. Metzger ◽

...

Keyword(s):

Influenza Virus ◽

Streptococcus Pneumoniae ◽

Influenza Infection ◽

Airway Disease ◽

Allergic Airway Disease ◽

Bacterial Clearance ◽

Content Type ◽

Ifn Γ ◽

The Impact ◽

First Time

ABSTRACTFatal outcomes following influenza infection are often associated with secondary bacterial infections. Allergic airway disease (AAD) is known to influence severe complications from respiratory infections, and yet the mechanistic effect of AAD on influenza virus-Streptococcus pneumoniaecoinfection has not been investigated previously. We examined the impact of AAD on host susceptibility to viral-bacterial coinfections. We report that AAD improved survival during coinfection when viral-bacterial challenge occurred 1 week after AAD. Counterintuitively, mice with AAD had significantly deceased proinflammatory responses during infection. Specifically, both CD4+and CD8+T cell interferon gamma (IFN-γ) responses were suppressed following AAD. Resistance to coinfection was also associated with strong transforming growth factor β1 (TGF-β1) expression and increased bacterial clearance. Treatment of AAD mice with IFN-γ or genetic deletion of TGF-β receptor II expression reversed the protective effects of AAD. Using a novel triple-challenge model system, we show for the first time that AAD can provide protection against influenza virus-S. pneumoniaecoinfection through the production of TGF-β that suppresses the influenza virus-induced IFN-γ response, thereby preserving antibacterial immunity.IMPORTANCEAsthma has become one of the most common chronic diseases and has been identified as a risk factor for developing influenza. However, the impact of asthma on postinfluenza secondary bacterial infection is currently not known. Here, we developed a novel triple-challenge model of allergic airway disease, primary influenza infection, and secondaryStreptococcus pneumoniaeinfection to investigate the impact of asthma on susceptibility to viral-bacterial coinfections. We report for the first time that mice recovering from acute allergic airway disease are highly resistant to influenza-pneumococcal coinfection and that this resistance is due to inhibition of influenza virus-mediated impairment of bacterial clearance. Further characterization of allergic airway disease-associated resistance against postinfluenza secondary bacterial infection may aid in the development of prophylactic and/or therapeutic treatment against coinfection.

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Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and ChronicAspergillus fumigatusExposure

Infection and Immunity ◽

10.1128/iai.00944-17 ◽

2018 ◽

Vol 86 (7) ◽

Cited By ~ 8

Author(s):

Jaleesa M. Garth ◽

Joseph J. Mackel ◽

Kristen M. Reeder ◽

Jonathan P. Blackburn ◽

Chad W. Dunaway ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Responses ◽

Asthma Severity ◽

Immune Defense ◽

Negative Regulator ◽

Prostaglandin E ◽

Fungal Cell ◽

Content Type ◽

Acidic Mammalian Chitinase ◽

The Impact

ABSTRACTChitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) (Chia) deficiency on host defense during acute exposure to the fungal pathogenAspergillus fumigatusas well as its contribution toA. fumigatus-associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels inA. fumigatusconidia, which emerged at the highest level during hyphal transition. In response to acuteA. fumigatuschallenge,Chia−/−mice unexpectedly demonstrated lowerA. fumigatuslung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin-33 (IL-33) levels yet increased IL-1β and prostaglandin E2(PGE2) production, a phenotype that we reported previously to promote the induction of IL-17A and IL-22. During chronicA. fumigatusexposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses.

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Duodenal Helminth Infection Alters Barrier Function of the Colonic Epithelium via Adaptive Immune Activation

Infection and Immunity ◽

10.1128/iai.01123-10 ◽

2011 ◽

Vol 79 (6) ◽

pp. 2285-2294 ◽

Cited By ~ 33

Author(s):

Chien-wen Su ◽

Yue Cao ◽

Jess Kaplan ◽

Mei Zhang ◽

Wanglin Li ◽

...

Keyword(s):

Immune Response ◽

Barrier Function ◽

Helminth Infection ◽

Scid Mice ◽

Ultrastructural Changes ◽

Intestinal Helminth ◽

Epithelial Barrier ◽

Epithelial Permeability ◽

Content Type ◽

The Impact

ABSTRACTChronic infection with intestinal helminth parasites is a major public health problem, particularly in the developing world, and can have significant effects on host physiology and the immune response to other enteric infections and antigens. The mechanisms underlying these effects are not well understood. In the current study, we investigated the impact of infection with the murine nematode parasiteHeligmosomoides polygyrus, which resides in the duodenum, on epithelial barrier function in the colon. We found thatH. polygyrusinfection produced a significant increase in colonic epithelial permeability, as evidenced by detection of elevated serum levels of the tracer horseradish peroxidase following rectal administration. This loss of normal barrier function was associated with clear ultrastructural changes in the tight junctions of colonic epithelial cells and an alteration in the expression and distribution of the junctional protein E-cadherin. These parasite-induced abnormalities were not observed in SCID mice but did occur in SCID mice that were adoptively transferred with wild-type T cells, indicating a requirement for adaptive immunity. Furthermore, the helminth-induced increase in gut permeability was not seen in STAT6 knockout (KO) mice. Taken together, the results demonstrate that one of the mechanisms by which helminths exert their effects involves the lymphocyte- and STAT6-dependent breakdown of the intestinal epithelial barrier. This increase in epithelial permeability may facilitate the movement of lumenal contents across the mucosa, thus helping to explain how helminth infection can alter the immune response to enteric antigens.

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