SARS-CoV-2 rapidly adapts in aged BALB/c mice and induces typical pneumonia

Age is a risk factor for coronavirus disease 2019 (COVID-19) associated morbidity and mortality in humans; hence, in this study, we compared the course of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) infection in young and aged BALB/c mice. We found that SARS-CoV-2 isolates replicated in the respiratory tracts of 12-month-old (aged) mice and caused pathological features of pneumonia upon intranasal infection. In contrast, rapid viral clearance was observed 5 days following infection in 2-month-old (young) mice with no evidence of pathological changes in the lungs. Infection with SARS-CoV-2 elicited significantly upregulated production of cytokines, especially interleukin 6 and interferon gamma, in aged mice; whereas this response was much weaker in young mice. Subsequent challenge of infected aged BALB/c mice with SARS-CoV-2 resulted in neutralized antibody responses, a significantly reduced viral burden in the lungs, and inflammation mitigation. Deep sequencing showed a panel of mutations potentially associated with the enhanced infection in aged BALB/c mice, such as the Q498H mutations which are located at the receptor binding domain (RBD) of the spike (S) protein. We further found that the isolates can not only multiply in the respiratory tract of mice but also cause disease in aged mice. Overall, viral replication and rapid adaption in aged BALB/c mice were associated with pneumonia, confirming that the age-related susceptibility to SARS-CoV-2 in mice resembled that in humans. Importance Aged BALB/c model are in use as a model of disease caused by SARS-CoV-2. Our research demonstrated SARS-CoV-2 can rapidly adapt in aged BALB/c mice through causing mutations at the RBD of the S protein. Moreover, SARS-CoV-2-infected aged BALB/c mice indicated that alveolar damage, interstitial pneumonia, and inflammatory immune responses were similar to the clinical manifestations of human infections. Therefore, our aged BALB/c challenge model will be useful for further understanding the pathogenesis of SARS-CoV-2 and for testing vaccines and antiviral agents.

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IL-10–producing Tfh cells accumulate with age and link inflammation with age-related immune suppression

Science Advances ◽

10.1126/sciadv.abb0806 ◽

2020 ◽

Vol 6 (31) ◽

pp. eabb0806 ◽

Cited By ~ 1

Author(s):

Maha Almanan ◽

Jana Raynor ◽

Ireti Ogunsulire ◽

Anna Malyshkina ◽

Shibabrata Mukherjee ◽

...

Keyword(s):

Immune Responses ◽

Immune Suppression ◽

Serum Levels ◽

Normal Serum ◽

Antibody Responses ◽

Regulatory Cells ◽

Aged Mice ◽

Follicular Helper ◽

Forkhead Box ◽

Age Related

Aging results in profound immune dysfunction, resulting in the decline of vaccine responsiveness previously attributed to irreversible defects in the immune system. In addition to increased interleukin-6 (IL-6), we found aged mice exhibit increased systemic IL-10 that requires forkhead box P3–negative (FoxP3−), but not FoxP3+, CD4+T cells. Most IL-10–producing cells manifested a T follicular helper (Tfh) phenotype and required the Tfh cytokines IL-6 and IL-21 for their accrual, so we refer to them as Tfh10 cells. IL-21 was also required to maintain normal serum levels of IL-6 and IL-10. Notably, antigen-specific Tfh10 cells arose after immunization of aged mice, and neutralization of IL-10 receptor signaling significantly restored Tfh-dependent antibody responses, whereas depletion of FoxP3+ regulatory and follicular regulatory cells did not. Thus, these data demonstrate that immune suppression with age is reversible and implicate Tfh10 cells as an intriguing link between “inflammaging” and impaired immune responses with age.

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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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Antibody Responses to SARS-CoV-2 mRNA Vaccines Are Detectable in Saliva

Pathogens and Immunity ◽

10.20411/pai.v6i1.441 ◽

2021 ◽

Vol 6 (1) ◽

pp. 116-134

Author(s):

Thomas J. Ketas ◽

Devidas Chaturbhuj ◽

Victor M. Cruz Portillo ◽

Erik Francomano ◽

Encouse Golden ◽

...

Keyword(s):

Immune Responses ◽

Serum Antibody ◽

Cross Sectional Study ◽

Antibody Responses ◽

Target Cells ◽

Receptor Binding Domain ◽

Sectional Study ◽

Cross Sectional ◽

S Protein ◽

Iga Antibodies

The approved Pfizer and Moderna mRNA vaccines are well known to induce serum antibody responses to the SARS-CoV-2 Spike (S)-protein. However, their abilities to elicit mucosal immune responses have not been reported. Saliva antibodies represent mucosal responses that may be relevant to how mRNA vaccines prevent oral and nasal SARS-CoV-2 transmission. Here, we describe the outcome of a cross-sectional study on a healthcare worker cohort (WELCOME-NYPH), in which we assessed whether IgM, IgG, and IgA antibodies to the S-protein and its receptor-binding domain (RBD) were present in serum and saliva samples. Anti-S-protein IgG was detected in 14/31 and 66/66 of saliva samples from uninfected participants after vaccine doses-1 and -2, respectively. IgA antibodies to the S-protein were present in 40/66 saliva samples after dose 2. Anti-S-protein IgG was present in every serum sample from recipients of 2 vaccine doses. Vaccine-induced antibodies against the RBD were also frequently present in saliva and sera. These findings may help our understanding of whether and how vaccines may impede SARS-CoV-2 transmission, including to oral cavity target cells.

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P03.13 Age-induced changes in anti-tumor immunity alter the tumor immune infiltrate and reduce response to immune-oncology treatments

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.52 ◽

2020 ◽

Vol 8 (Suppl 2) ◽

pp. A27.2-A27

Author(s):

S Sitnikova ◽

M Morrow ◽

V Valge-Archer ◽

RW Wilkinson ◽

MJ Robinson ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Expression Profiles ◽

Receptor Expression ◽

Altered Expression ◽

Aged Mice ◽

Oncology Research ◽

Age Related ◽

Part Time ◽

Young Mice

BackgroundImmuno-Oncology research relies heavily on murine syngeneic tumor models. However, whilst the median age for a cancer diagnosis is 65 years or older, for practical purposes the majority of preclinical studies are conducted in young mice, despite the fact that ageing has been shown to have a significant impact on the immune response.Materials and MethodsUsing aged mice bearing CT26 tumors, we analysed how aging impacts the immune composition of the tumor, spleen and tumor-draining lymph nodes by flow cytometry.ResultsWe found many age-related changes between aged (60–72 weeks old) and young (6–8 weeks old) mice, such as a reduction in the naïve T cell population and a decreased CD8/Treg ratio in aged animals. Profiling of co-inhibitory and co-stimulatory receptor expression levels on immune cells in aged versus young mice also identified altered expression profiles in both the periphery and tumor. We hypothesised that these differences may contribute to impaired anti-cancer immune responses in aged mice. To investigate this, we compared the anti-tumor efficacy of immune checkpoint blockade (PD-L1 and CTLA-4) and T-cell costimulation (OX-40) in aged versus young mice. Our data demonstrate that aged mice retained their capacity to generate effective anti-tumor immune responses, albeit often attenuated when compared to the responses observed in young mice.ConclusionsThese differences highlight the potential importance of age-related immunological changes in assessing and refining the translational insights gained from preclinical mouse models.Disclosure InformationS. Sitnikova: A. Employment (full or part-time); Significant; AstraZeneca. M. Morrow: A. Employment (full or part-time); Significant; AstraZeneca. V. Valge-Archer: A. Employment (full or part-time); Significant; AstraZeneca. R.W. Wilkinson: A. Employment (full or part-time); Significant; AstraZeneca. M.J. Robinson: A. Employment (full or part-time); Significant; AstraZeneca. S.J. Dovedi: A. Employment (full or part-time); Significant; AstraZeneca.

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Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00065-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Miwa Nahata ◽

Sachiko Mogami ◽

Hitomi Sekine ◽

Seiichi Iizuka ◽

Naoto Okubo ◽

...

Keyword(s):

Amino Acid ◽

Energy Homeostasis ◽

Mitochondrial Dynamics ◽

Negative Regulator ◽

Aged Mice ◽

Glucose Levels ◽

Therapeutic Benefits ◽

Age Related ◽

Daily Food ◽

Young Mice

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

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Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2

Wiener klinische Wochenschrift ◽

10.1007/s00508-021-01922-y ◽

2021 ◽

Author(s):

Peter G. Kremsner ◽

Philipp Mann ◽

Arne Kroidl ◽

Isabel Leroux-Roels ◽

Christoph Schindler ◽

...

Keyword(s):

Immune Responses ◽

Vaccine Candidate ◽

Phase 1 ◽

Lipid Nanoparticles ◽

Enzyme Linked Immunosorbent Assay ◽

Receptor Binding Domain ◽

Igg Antibodies ◽

Phase 1 Study ◽

S Protein ◽

Dosage Escalation

Summary Background We used the RNActive® technology platform (CureVac N.V., Tübingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilized form of SARS-CoV‑2 spike (S) protein encapsulated in lipid nanoparticles (LNP). Methods This is an interim analysis of a dosage escalation phase 1 study in healthy 18–60-year-old volunteers in Hannover, Munich and Tübingen, Germany, and Ghent, Belgium. After giving 2 intramuscular doses of CVnCoV or placebo 28 days apart we assessed solicited local and systemic adverse events (AE) for 7 days and unsolicited AEs for 28 days after each vaccination. Immunogenicity was measured as enzyme-linked immunosorbent assay (ELISA) IgG antibodies to SARS-CoV‑2 S‑protein and receptor binding domain (RBD), and SARS-CoV‑2 neutralizing titers (MN50). Results In 245 volunteers who received 2 CVnCoV vaccinations (2 μg, n = 47, 4 μg, n = 48, 6 μg, n = 46, 8 μg, n = 44, 12 μg, n = 28) or placebo (n = 32) there were no vaccine-related serious AEs. Dosage-dependent increases in frequency and severity of solicited systemic AEs, and to a lesser extent local AEs, were mainly mild or moderate and transient in duration. Dosage-dependent increases in IgG antibodies to S‑protein and RBD and MN50 were evident in all groups 2 weeks after the second dose when 100% (23/23) seroconverted to S‑protein or RBD, and 83% (19/23) seroconverted for MN50 in the 12 μg group. Responses to 12 μg were comparable to those observed in convalescent sera from known COVID-19 patients. Conclusion In this study 2 CVnCoV doses were safe, with acceptable reactogenicity and 12 μg dosages elicited levels of immune responses that overlapped those observed in convalescent sera.

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Cross-reactive antibody response to mRNA SARS-CoV-2 vaccine after recent COVID-19-specific monoclonal antibody therapy

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab420 ◽

2021 ◽

Author(s):

Stacey Schultz-Cherry ◽

Maureen A McGargill ◽

Paul G Thomas ◽

Jeremie H Estepp ◽

Aditya H Gaur ◽

...

Keyword(s):

Monoclonal Antibody ◽

Immune Responses ◽

Antibody Response ◽

Antibody Therapy ◽

Antibody Responses ◽

Monoclonal Antibody Therapy ◽

Receptor Binding Domain ◽

Specific Monoclonal Antibody ◽

Vaccine Failure ◽

Reactive Antibody

Abstract Efficacy of COVID-19 vaccines administered after COVID-19-specific monoclonal antibody is unknown, and ‘antibody interference’ might hinder immune responses leading to vaccine failure. In an IRB-approved prospective study, we found that an individual who received mRNA COVID-19 vaccination <40 days after COVID-19-specific monoclonal antibody therapy for symptomatic COVID-19 had similar post-vaccine antibody responses to SARS-CoV-2 receptor binding domain (RBD), for four important SARS-CoV-2 variants (B.1, B.1.1.7, B.1.351 and P.1), as other participants who were also vaccinated following COVID-19. Vaccination against COVID-19 shortly after COVID-19-specific monoclonal antibody can boost and expand antibody protection, questioning the need to delay vaccination in this setting.

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Aging Dampens the Intestinal Innate Immune Response during Severe Clostridioides difficile Infection and Is Associated with Altered Cytokine Levels and Granulocyte Mobilization

Infection and Immunity ◽

10.1128/iai.00960-19 ◽

2020 ◽

Vol 88 (6) ◽

Author(s):

Lisa Abernathy-Close ◽

Michael G. Dieterle ◽

Kimberly C. Vendrov ◽

Ingrid L. Bergin ◽

Krishna Rao ◽

...

Keyword(s):

Immune Responses ◽

Disease Severity ◽

Immune Cell ◽

White Blood Cells ◽

Host Susceptibility ◽

Simultaneous Increase ◽

Content Type ◽

Aged Mice ◽

Clostridioides Difficile ◽

Age Related

ABSTRACT Clostridioides (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 specific impact of aging on immune responses during C. difficile infection remains to be well described. This study explores the effect of age on cellular and cytokine immune responses during C. difficile infection. Young mice (2 to 3 months old) and aged mice (22 to 28 months old) were rendered susceptible to C. difficile infection with the antibiotic cefoperazone and then infected with C. difficile strains with varied disease-causing potentials. We observe that the host age and the infecting C. difficile strain influenced the severity of disease associated with infection. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the ceca and colons 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, with a corresponding decrease in circulating CXCL1, an important neutrophil recruiter and activator. Interestingly, this lack of intestinal granulocyte response in aged mice during severe C. difficile infection was accompanied by a simultaneous increase in circulating white blood cells, granulocytes, and interleukin 17A (IL-17A). These findings demonstrate that age-related alterations in neutrophils and eosinophils and systemic cytokine and chemokine responses are associated with severe C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.

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Protective Effects of Curcumin and Broccoli Seed Extract Against Age-Related Bone Loss in Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzaa040_046 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 46-46

Author(s):

Jing Li ◽

Dong Zhang ◽

Yiping Ren ◽

Zhongdong Qiao ◽

Doug Stevenson ◽

...

Keyword(s):

Bone Loss ◽

Seed Extract ◽

Control Group ◽

Protective Effects ◽

Trabecular Thickness ◽

Time Points ◽

Aged Mice ◽

Funding Sources ◽

Age Related ◽

Young Mice

Abstract Objectives Age-related bone loss occurs in both men and women, and is the leading cause of elderly disability. An age-related bone loss model was established in mice to investigate the protective effects of curcumin and broccoli seed extract. Methods 20 young (6-month-old) male C57BL/6 J mice after administration with vehicle once daily were sacrificed at four time points: day 0, 30, 60 and 90. 8 out of the 109 aged (18-month-old) male C57BL/6 J mice were sacrificed at the beginning and used as control. The rest of these aged mice were then randomly divided into four groups: one group served as control (vehicle), the other three groups were administrated with curcumin (CMN) and/or broccoli seed extract (BSE) by oral gavage. Mice in each group were sacrificed at four time points: day 0, 30, 60 and 90. L2 vertebrae of mice were fixed with paraformaldehyde and scanned with a Scanco Medical μCT40 scanner. Quantitative analyses of bone volume (BV), tissue volume (TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular spacing (Tb.Sp) were performed with the Scanco Medical's software. Results BV/TV of the young mice group were significantly higher compared to the aged mice group at all four time points. Similarly, Tb.N and Tb.Th were also higher in the young mice group compared to the aged mice group. In contrast, Tb.Sp was lower in the young mice group. When comparing different groups in the aged mice, we found that mice administered with CMN had a higher BV/TV value compared to the mice in the control group at all three time points. Such a difference is significant by day 30. The mice administered with combined CMN and BSE also showed significant increase in BV/TV on day 30. For Tb.N, both mice administered with either CMN or BSE had higher values at all three time points. But no obvious difference in Tb.N was found for mice administered with combined CMN and BSE. For Tb.Th, both mice administered with CMN and with combined CMN and BSE had higher values compared to the control. For Tb.Sp, both mice administered with either CMN or BSE had lower values compared to the control. Conclusions This study showed that curcumin could slow down bone loss in the mouse model. There is no obvious positive effect with broccoli seed extract or with curcumin and broccoli seed extract combined. The curcumin used in this study may shed light on the alleviation of bone loss in humans. Funding Sources Nu Skin Enterprises.

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Immunogenicity of SCB-2019 COVID-19 Vaccine Compared to Four Approved Vaccines

10.21203/rs.3.rs-902086/v1 ◽

2021 ◽

Author(s):

Donna Ambrosino ◽

Htay Htay Han ◽

Branda Hu ◽

Joshua Liang ◽

Ralf Clemens ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Vaccine Efficacy ◽

Antibody Responses ◽

Original Strain ◽

S Protein ◽

Binding Antibody ◽

Alpha Variant ◽

Efficacy Studies

Abstract A significant correlation has been shown between the binding antibody responses against original SARS-CoV-2-S-protein all performed in one laboratory and vaccine efficacy of four approved COVID-19 vaccines. We therefore assessed the immune response against original SARS-CoV-2 elicited by the adjuvanted S-Trimer vaccine, SCB-2019 + CpG/alum, in the same assay and laboratory. When compared with four approved vaccines immune responses to SCB-2019 predicted 81% − 94% efficacy against the original strain and 75–94% against the Alpha variant (B.1.1.7). Immunogenicity comparisons to original strain and variants of concern (VOC) should be considered as a basis for authorization of vaccines because efficacy studies now have predominantly VOC cases.

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