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

Mapping Intimacies ◽

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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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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Should immunocontraception be used for wildlife population management?

Australian Mammalogy ◽

10.1071/am04061 ◽

2004 ◽

Vol 26 (1) ◽

pp. 61 ◽

Cited By ~ 3

Author(s):

DW Cooper

Keyword(s):

Immune Response ◽

New Zealand ◽

Immune Responses ◽

Fundamental Problem ◽

Public Perceptions ◽

Published Data ◽

Red Foxes ◽

European Rabbits ◽

Selection For ◽

Self Antigens

Immunocontraception involves eliciting an immune response against eggs, sperm or hormones so that successful reproduction is prevented. Work in Australasia is aimed at European rabbits (Oryctolagus cuniculus), red foxes (Vulpes vulpes), house mice (Mus musculus), common brushtail possums (Trichosurus vulpecula), koalas (Phascolartcos cinereus) and kangaroos (Macropus spp.), with the vaccines involved all containing self antigens or their relatives. Two fundamental problems have been inadequately addressed in this research. The first problem is that it is difficult to obtain strong immune responses against self antigens and so the vaccines may be ineffective. Most published data on the effect of immunocontraceptives on reproduction involve the use of an adjuvant of which there are many kinds. The materials enhance the immune response greatly. The most frequently used is Freund?s adjuvant which can cause chronic suffering. Its use on wildlife will lead to very negative public perceptions. There has been no convincing demonstration that successful immunocontraception is possible with any method of vaccination likely to be used in the field, if success is defined as contraception of a proportion of the population high enough for management requirements. If it is assumed that success can be achieved, the second fundamental problem arises with two potential consequences. Even with adjuvant, a substantial minority of the vaccinated animals remains fertile. The first consequence is that since failure to be contracepted is likely to be in part genetic, there is likely to be rapid selection for these non-responders. The method will become ineffective in a few generations. The second problem is that the offspring of the animals which breed will have altered immune responses. Their capacities to respond to their own pathogens or to harbor pathogens of other species in the same ecosystem are likely to be changed. The presence of chlamydia in P. cinereus and bovine tuberculosis in New Zealand T. vulpecula means that responses to these pathogens would have to be studied in offspring of immunocontracepted parents to ensure that the offspring were not more susceptible to them. New Zealand intentions to put an immunocontraceptive into a T. vulpecula gut worm must be viewed with caution by Australia. The eggs of transgenic worms will be easily transplanted either accidentally or deliberately back into Australia, and so infect T. vulpecula in Australia.

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Possible influence of anti-vector immunity and SARS-CoV-2 variants on efficacy of ChAdOx1 nCoV-19 vaccine and the proposal of a new pharmacotherapy

10.22541/au.162141142.21655505/v1 ◽

2021 ◽

Author(s):

Loris Zamal ◽

Marco Rocchi

Keyword(s):

Immune Response ◽

Longitudinal Studies ◽

Selective Pressure ◽

Response Prediction ◽

Published Data ◽

Zinc Metalloprotease ◽

Preventive Actions ◽

The Moment ◽

The Impact

The present work analyses in detail the published data on ChAdOx1 nCoV-19 vaccine and provides arguments for the involvement of anti-vector immunity and of SARS-CoV-2 variants on the efficacy of ChAdOx1 nCoV-19 vaccine. First, it is suggested that anti-vector immunity takes place as the regimen of homologous vaccination with ChAdOx1 nCoV-19 vaccine is applied and interferes with efficacy of the vaccine when the interval between prime and boost doses is less than three months. Second, longitudinal studies suggest that ChAdOx1 nCoV-19 vaccine provides sub-optimal efficacy against UK variant of SARS-CoV-2, which appears to have an increased transmissibility over the ancestral SARS-CoV-2 among vaccinated people. At the moment, ChAdOx1 nCoV-19 vaccine is able to reduce the severity of symptoms and transmissibility; however, if the vaccinated individuals do not maintain everyday preventive actions, they could turn into potential spreaders, thus accelerating the process of generation of new viral variants due to the selective pressure of immune response. Prediction and possible consequences of the SARS-CoV-2 evolution and repeated anti-SARS-CoV-2 vaccinations are discussed. Since the impact of emerging SARS-CoV-2 variants suggests that vaccines are unlikely to be effective in quickly solving the pandemic crisis, it is highlighted the need to keep searching for new and more efficacious pharmacotherapy for COVID-19, such as those targeting ACE2 and ADAM17 zinc-metalloprotease activities.

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

mSphere ◽

10.1128/msphere.00074-20 ◽

2020 ◽

Vol 5 (2) ◽

Author(s):

Moon H. Nahm ◽

Jigui Yu ◽

Jiri Vlach ◽

Maor Bar-Peled

Keyword(s):

Immune Response ◽

Streptococcus Pneumoniae ◽

Immune Responses ◽

Pneumococcal Vaccine ◽

Cross Reactivity ◽

Food Plants ◽

Content Type ◽

Plant Foods ◽

Vaccine Responses ◽

The Impact

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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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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Prion propagation in mice lacking central nervous system NF-κB signalling

Journal of General Virology ◽

10.1099/vir.0.83622-0 ◽

2008 ◽

Vol 89 (6) ◽

pp. 1545-1550 ◽

Cited By ~ 16

Author(s):

C. Julius ◽

M. Heikenwalder ◽

P. Schwarz ◽

A. Marcel ◽

M. Karin ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Immune Responses ◽

Published Data ◽

Histopathological Changes ◽

Prion Infection ◽

Prion Propagation ◽

Proliferation Regulation ◽

The Impact ◽

The Brain

Prions induce highly typical histopathological changes including cell death, spongiosis and activation of glia, yet the molecular pathways leading to neurodegeneration remain elusive. Following prion infection, enhanced nuclear factor-κB (NF-κB) activity in the brain parallels the first pathological changes. The NF-κB pathway is essential for proliferation, regulation of apoptosis and immune responses involving induction of inflammation. The IκB kinase (IKK) signalosome is crucial for NF-κB signalling, consisting of the catalytic IKKα/IKKβ subunits and the regulatory IKKγ subunit. This study investigated the impact of NF-κB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKβ or IKKγ in nearly all neuroectodermal cells, including neurons, astrocytes and oligodendrocytes, and in mice containing a non-phosphorylatable IKKα subunit (IKKα AA/AA). In contrast to previously published data, the observed results showed no evidence supporting the hypothesis that impaired NF-κB signalling in the CNS impacts on prion pathogenesis.

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Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

Frontiers in Medicine ◽

10.3389/fmed.2021.625763 ◽

2021 ◽

Vol 8 ◽

Author(s):

Shaun Pienkos ◽

Natalia Gallego ◽

David F. Condon ◽

Alejandro Cruz-Utrilla ◽

Nuria Ochoa ◽

...

Keyword(s):

Immune Response ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Genetic Variants ◽

Vascular Remodeling ◽

Biliary Cirrhosis ◽

Pulmonary Vascular Remodeling ◽

Pulmonary Arterial ◽

The Impact ◽

Healthy Lung

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling and right heart failure. Specific genetic variants increase the incidence of PAH in carriers with a family history of PAH, those who suffer from certain medical conditions, and even those with no apparent risk factors. Inflammation and immune dysregulation are related to vascular remodeling in PAH, but whether genetic susceptibility modifies the PAH immune response is unclear. TNIP2 and TRAF2 encode for immunomodulatory proteins that regulate NF-κB activation, a transcription factor complex associated with inflammation and vascular remodeling in PAH.Methods: Two unrelated families with PAH cases underwent whole-exome sequencing (WES). A custom pipeline for variant prioritization was carried out to obtain candidate variants. To determine the impact of TNIP2 and TRAF2 in cell proliferation, we performed an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay on healthy lung pericytes transfected with siRNA specific for each gene. To measure the effect of loss of TNIP2 and TRAF2 on NF-kappa-beta (NF-κB) activity, we measured levels of Phospho-p65-NF-κB in siRNA-transfected pericytes using western immunoblotting.Results: We discovered a novel missense variant in the TNIP2 gene in two affected individuals from the same family. The two patients had a complex form of PAH with interatrial communication and scleroderma. In the second family, WES of the proband with PAH and primary biliary cirrhosis revealed a de novo protein-truncating variant in the TRAF2. The knockdown of TNIP2 and TRAF2 increased NF-κB activity in healthy lung pericytes, which correlated with a significant increase in proliferation over 24 h.Conclusions: We have identified two rare novel variants in TNIP2 and TRAF2 using WES. We speculate that loss of function in these genes promotes pulmonary vascular remodeling by allowing overactivation of the NF-κB signaling activity. Our findings support a role for WES in helping identify novel genetic variants associated with dysfunctional immune response in PAH.

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Aging dampens the intestinal innate immune response during Clostridioides difficile infection and is associated with altered intestinal eosinophil mobilization

10.1101/2020.01.02.893461 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lisa Abernathy-Close ◽

Michael G. Dieterle ◽

Kimberly C. Vendrov ◽

Ingrid L. Bergin ◽

Vincent B. Young

Keyword(s):

Immune Response ◽

Immune Responses ◽

Disease Severity ◽

Advanced Age ◽

Simultaneous Increase ◽

Aged Mice ◽

Age Related ◽

Cellular Immune ◽

The Impact ◽

Young Mice

ABSTRACTClostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the impact of aging on the cellular immune response associated with C. difficile infection in the setting of advanced age remains to be well described. This study explores the effect of age on cellular immune responses in C. difficile infection as well as disease severity. Young adult mice (2-3 months old) and aged mice (22-28 months old) were rendered susceptible to C. difficile infection with cefoperazone and then infected with C. difficile strains of varying disease-causing potential. Aged mice infected with C. difficile develop more severe clinical disease, compared to young mice. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the cecum and colon of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice. Interestingly, while C. difficile infection in young mice was associated with a robust increase in cecal and colonic eosinophils, there was a complete lack of an intestinal eosinophil response in aged counterparts accompanied by a simultaneous increase in blood eosinophils with severe disease. These findings demonstrate that age-related alterations in immune responses are associated with significantly worse C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.

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The influence of the gut microbiota on influenza vaccine-induced immunity

10.26686/wgtn.17131847 ◽

2021 ◽

Author(s):

◽

Anna Mooney

Keyword(s):

Immune Response ◽

Gut Microbiota ◽

Immune Responses ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

Antibody Production ◽

Host Immune System ◽

Viral Control ◽

Nutritional Interventions ◽

The Impact

<p>Currently, annual vaccination is widely considered the most effective method for preventing and controlling influenza virus infection. However, many individuals mount suboptimal immune responses to vaccination and the factors leading to poor immune responses are yet to be elucidated. Interestingly, it has been proposed that microorganisms that inhabit the intestinal tract, the gut microbiota, can profoundly influence many facets of the host immune system, including the strength of the immune response to influenza vaccination. In line with these observations, we observed that short-term administration of antibiotics drastically reduced influenza vaccine-specific antibody production. In particular, antibiotic treatment diminished the frequency and activation status of multiple myeloid cell subsets in the draining lymph nodes at steady-state and following vaccination, with associated impairments in B and TFH cell responses. Composition and function of gut microbiota communities can be rapidly altered through dietary changes. Therefore, the impact of potential prebiotic and probiotic nutritional interventions on the immune response to influenza vaccination and subsequent infection was assessed. No improvement in antibody responses to influenza vaccination was observed following the nutritional interventions studies. However, oral administration of a propolis formulation led to some improvement in viral control following infection. Collectively, this investigation indicates that alterations in microbial-associated signals leads to severe impairments in cellular responses crucial to humoral immunity and subsequent vaccine-induced antibody production. Furthermore, by altering the gut microbiota through dietary interventions, there is potential to improve immune responses to vaccination.</p>

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