Publications by authors named "Janko Nikolich-Zugich"

120 Publications

IL-6 can singlehandedly drive many features of frailty in mice.

Geroscience 2021 Feb 24. Epub 2021 Feb 24.

Department of Immunobiology, University of Arizona College of Medicine-Tucson, Tucson, AZ, USA.

Frailty is a geriatric syndrome characterized by age-related declines in function and reserve resulting in increased vulnerability to stressors. The most consistent laboratory finding in frail subjects is elevation of serum IL-6, but it is unclear whether IL-6 is a causal driver of frailty. Here, we characterize a new mouse model of inducible IL-6 expression (IL-6 mice) following administration of doxycycline (Dox) in food. In this model, IL-6 induction was Dox dose-dependent. The Dox dose that increased IL-6 levels to those observed in frail old mice directly led to an increase in frailty index, decrease in grip strength, and disrupted muscle mitochondrial homeostasis. Littermate mice lacking the knock-in construct failed to exhibit frailty after Dox feeding. Both naturally old mice and young Dox-induced IL-6 mice exhibited increased IL-6 levels in sera and spleen homogenates but not in other tissues. Moreover, Dox-induced IL-6 mice exhibited selective elevation in IL-6 but not in other cytokines. Finally, bone marrow chimera and splenectomy experiments demonstrated that non-hematopoietic cells are the key source of IL-6 in our model. We conclude that elevated IL-6 serum levels directly drive age-related frailty, possibly via mitochondrial mechanisms.
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http://dx.doi.org/10.1007/s11357-021-00343-zDOI Listing
February 2021

Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury.

Transl Res 2020 Dec 20. Epub 2020 Dec 20.

College of Medicine, University of Arizona Health Sciences, Tucson, Arizona. Electronic address:

Approximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies.
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http://dx.doi.org/10.1016/j.trsl.2020.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749994PMC
December 2020

Immunity to acute virus infections with advanced age.

Curr Opin Virol 2021 Feb 4;46:45-58. Epub 2020 Nov 4.

Department of Immunobiology and the University of Arizona Center on Aging, University of Arizona College of Medicine - Tucson, Tucson, AZ 85724, USA.

New infections in general, and new viral infections amongst them, represent a serious challenge to an older organism. This review discusses the age-related alterations in responsiveness to infection from the standpoint of virus:host relationship and the host physiological whole-organism and specific immune response to the virus. Changes with age in the innate and adaptive immune system homeostasis and function are reviewed briefly. This is followed by a review of specific alterations and defects in the response of older organisms (chiefly mice and humans) to acute (particularly emerging and re-emerging) viral infections, with a very brief summary of the response to latent persistent infections. Finally, we provide a brief summary of the perspectives for possible interventions to enhance antiviral immunity.
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http://dx.doi.org/10.1016/j.coviro.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979450PMC
February 2021

Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity.

Immunity 2020 11 14;53(5):925-933.e4. Epub 2020 Oct 14.

Department of Immunobiology, University of Arizona College of Medicine, Tucson, Tucson, AZ, USA; BIO5 Institute, University of Arizona, Tucson, AZ, USA. Electronic address:

We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.immuni.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554472PMC
November 2020

Affinity-Restricted Memory B Cells Dominate Recall Responses to Heterologous Flaviviruses.

Immunity 2020 Nov 2;53(5):1078-1094.e7. Epub 2020 Oct 2.

Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA. Electronic address:

Memory B cells (MBCs) can respond to heterologous antigens either by molding new specificities through secondary germinal centers (GCs) or by selecting preexisting clones without further affinity maturation. To distinguish these mechanisms in flavivirus infections and immunizations, we studied recall responses to envelope protein domain III (DIII). Conditional deletion of activation-induced cytidine deaminase (AID) between heterologous challenges of West Nile, Japanese encephalitis, Zika, and dengue viruses did not affect recall responses. DIII-specific MBCs were contained mostly within the plasma-cell-biased CD80 subset, and few GCs arose following heterologous boosters, demonstrating that recall responses are confined by preexisting clonal diversity. Measurement of monoclonal antibody (mAb) binding affinity to DIII proteins, timed AID deletion, single-cell RNA sequencing, and lineage tracing experiments point to selection of relatively low-affinity MBCs as a mechanism to promote diversity. Engineering immunogens to avoid this MBC diversity may facilitate flavivirus-type-specific vaccines with minimized potential for infection enhancement.
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http://dx.doi.org/10.1016/j.immuni.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677180PMC
November 2020

Cytomegalovirus and Your Health: Not a Matter of the Heart, Nor of Life and Death.

J Infect Dis 2021 Feb;223(2):181-183

Department of Immunobiology and the University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA.

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http://dx.doi.org/10.1093/infdis/jiaa481DOI Listing
February 2021

Antibody Responses to SARS-CoV-2: Let's Stick to Known Knowns.

J Immunol 2020 11 4;205(9):2342-2350. Epub 2020 Sep 4.

Department of Immunobiology, University of Arizona College of Medicine-Tucson, Tucson, AZ 85724;

The scale of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has thrust immunology into the public spotlight in unprecedented ways. In this article, which is part opinion piece and part review, we argue that the normal cadence by which we discuss science with our colleagues failed to properly convey likelihoods of the immune response to SARS-CoV-2 to the public and the media. As a result, biologically implausible outcomes were given equal weight as the principles set by decades of viral immunology. Unsurprisingly, questionable results and alarmist news media articles have filled the void. We suggest an emphasis on setting expectations based on prior findings while avoiding the overused approach of assuming nothing. After reviewing Ab-mediated immunity after coronavirus and other acute viral infections, we posit that, with few exceptions, the development of protective humoral immunity of more than a year is the norm. Immunity to SARS-CoV-2 is likely to follow the same pattern.
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http://dx.doi.org/10.4049/jimmunol.2000839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578055PMC
November 2020

Corrigendum: Defective Transcriptional Programming of Effector CD8 T Cells in Aged Mice Is Cell-Extrinsic and Can Be Corrected by Administration of IL-12 and IL-18.

Front Immunol 2020 28;11:1367. Epub 2020 Jul 28.

Department of Immunobiology and the University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, Tucson, AZ, United States.

[This corrects the article DOI: 10.3389/fimmu.2019.02206.].
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http://dx.doi.org/10.3389/fimmu.2020.01367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402194PMC
July 2020

Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure.

medRxiv 2020 Aug 15. Epub 2020 Aug 15.

Department of Immunobiology, University of Arizona College of Medicine - Tucson, Tucson, AZ, USA.

We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.08.14.20174490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430613PMC
August 2020

Correction to: SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes.

Geroscience 2020 06;42(3):1013

University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, P.O. Box 249221, 1501 N. Campbell Ave, Tucson, AZ, 8524, USA.

The affiliation of the second author (Kenneth S. Knox) should have been Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA instead of Department of Medicine, University of Arizona-Phoenix, Phoenix, AZ 85004, USA.
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http://dx.doi.org/10.1007/s11357-020-00193-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196177PMC
June 2020

SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes.

Geroscience 2020 04 10;42(2):505-514. Epub 2020 Apr 10.

University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, P.O. Box 249221, 1501 N. Campbell Ave, Tucson, AZ, 8524, USA.

SARS-CoV-2 virus, the causative agent of the coronavirus infectious disease-19 (COVID-19), is taking the globe by storm, approaching 500,000 confirmed cases and over 21,000 deaths as of March 25, 2020. While under control in some affected Asian countries (Taiwan, Singapore, Vietnam), the virus demonstrated an exponential phase of infectivity in several large countries (China in late January and February and many European countries and the USA in March), with cases exploding by 30-50,000/day in the third and fourth weeks of March, 2020. SARS-CoV-2 has proven to be particularly deadly to older adults and those with certain underlying medical conditions, many of whom are of advanced age. Here, we briefly review the virus, its structure and evolution, epidemiology and pathogenesis, immunogenicity and immune, and clinical response in older adults, using available knowledge on SARS-CoV-2 and its highly pathogenic relatives MERS-CoV and SARS-CoV-1. We conclude by discussing clinical and basic science approaches to protect older adults against this disease.
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http://dx.doi.org/10.1007/s11357-020-00186-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145538PMC
April 2020

Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging.

Geroscience 2020 04 11;42(2):495-504. Epub 2020 Mar 11.

Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.

Cytomegalovirus (CMV) is one of the largest and most ubiquitous latent persistent viruses. Most humans are infected with CMV early in life, and all immunocompetent humans spend several decades living with CMV. In the vast majority of the hosts, CMV does not cause manifest disease, and CMV therefore can be considered part of normal aging for 50-90% of the human population worldwide. Experimental, clinical, and epidemiological studies suggest that CMV carriage can have nuanced outcomes, including both potentially harmful and potentially beneficial impacts on the host. We here present a summary of the 7th International Workshop on CMV and Immunosenescence, covering various aspects of the interplay between CMV and its mammalian hosts in the context of virus spread, immune evasion, antiviral immunity, as well as the impact on health span and aging.
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http://dx.doi.org/10.1007/s11357-020-00170-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205956PMC
April 2020

Defects in Antiviral T Cell Responses Inflicted by Aging-Associated miR-181a Deficiency.

Cell Rep 2019 11;29(8):2202-2216.e5

Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94306, USA. Electronic address:

Generation of protective immunity to infections and vaccinations declines with age. Studies in healthy individuals have implicated reduced miR-181a expression in T cells as contributing to this defect. To understand the impact of miR-181a expression on antiviral responses, we examined LCMV infection in mice with miR-181ab1-deficient T cells. We found that miR-181a deficiency delays viral clearance, thereby biasing the immune response in favor of CD4 over CD8 T cells. Antigen-specific CD4 T cells in mice with miR-181a-deficient T cells expand more and have a broader TCR repertoire with preferential expansion of high-affinity T cells than in wild-type mice. Importantly, generation of antigen-specific miR-181a-deficient CD8 effector T cells is particularly impaired, resulting in lower frequencies of CD8 T cells in the liver even at time points when the infection has been cleared. Consistent with the mouse model, CD4 memory T cells in individuals infected with West Nile virus at older ages tend to be more frequent and of higher affinity.
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http://dx.doi.org/10.1016/j.celrep.2019.10.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957231PMC
November 2019

Defective Transcriptional Programming of Effector CD8 T Cells in Aged Mice Is Cell-Extrinsic and Can Be Corrected by Administration of IL-12 and IL-18.

Front Immunol 2019 18;10:2206. Epub 2019 Sep 18.

Department of Immunobiology and the University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, Tucson, AZ, United States.

In response to infection with intracellular microorganisms, old mice mobilize decreased numbers of antigen-specific CD8 T cells with reduced expression of effector molecules and impaired cytolytic activity. Molecular mechanisms behind these defects and the cell-intrinsic (affecting naïve CD8 T cells themselves) vs. extrinsic, microenvironmental origin of such defects remain unclear. Using reciprocal transfer experiments of highly purified naïve T cells from adult and old transgenic OT-1 mice, we decisively show that the dominant effect is cell-extrinsic. Naïve adult OT-1 T cells failed to expand and terminally differentiate in the old organism infected with -OVA. This defect was preceded by blunted expression of the master transcription factor T-bet and impaired glycolytic switch when T cells are primed in the old organism. However, both old and adult naïve CD8 T cells proliferated and produced effector molecules to a similar extent when stimulated with polyclonal stimuli, as well as when transferred into adult recipients. Multiple inflammatory cytokines with direct effects on T cell effector differentiation were decreased in spleens of old animals, particularly IL-12 and IL-18. Of note, treatment of mice with IL-12 and IL-18 on days 4-6 of infection reconstituted cytotoxic T cell response of aged mice to the level of adult. Therefore, critical cytokine signals which are underproduced in the old priming environment can restore proper transcriptional programming of old naïve CD8 T cells and improve immune defense against intracellular microorganisms.
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http://dx.doi.org/10.3389/fimmu.2019.02206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759569PMC
November 2020

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia.

PLoS Pathog 2019 06 20;15(6):e1007890. Epub 2019 Jun 20.

Department of Immunobiology and the University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, Tucson, AZ, United States of America.

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world's population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.
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http://dx.doi.org/10.1371/journal.ppat.1007890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605679PMC
June 2019

Menopause and FOXP3 Treg cell depletion eliminate female protection against T cell-mediated angiotensin II hypertension.

Am J Physiol Heart Circ Physiol 2019 08 17;317(2):H415-H423. Epub 2019 May 17.

Department of Physiology, University of Arizona, Tucson, Arizona.

Although it is known that the prevalence and severity of hypertension increases in women after menopause, the contribution of T cells to this process has not been explored. Although the immune system is both necessary and required for the development of angiotensin II (ANG II) hypertension in men, we have demonstrated that premenopausal women are protected from T cell-mediated hypertension. The goal of the current study was to test the hypotheses that ) female protection against T cell-mediated ANG II hypertension is eliminated following progression into menopause and ) T regulatory cells (Tregs) provide premenopausal protection against ANG II-induced hypertension. Menopause was induced in Rag-1 mice (via 4-vinylcyclohexene diepoxide), and all mice received a 14-day ANG II infusion. Donor CD3 T cells were adoptively transferred 3 wk before ANG II infusion. In the absence of T cells, systolic blood pressure responses to ANG II were similar to those seen in premenopausal mice (Δ12 mmHg). After adoptive transfer of T cells, ANG II significantly increased systolic blood pressure in postmenopausal females (Δ28 mmHg). A significant increase in F4/80 positive renal macrophages, an increase in renal inflammatory gene expression, along with a reduction in renal expression of mannose receptor C-type 1, a marker for M2 macrophages, accompanied the increase in systolic blood pressure (SBP). Flow cytometric analysis identified that Tregs were significantly decreased in the spleen and kidneys of Rag-1 menopausal mice versus premenopausal females, following ANG II infusion. In a validation study, an anti-CD25 antibody was used to deplete Tregs in premenopausal mice, which induced a significant increase in SBP. These results demonstrate that premenopausal protection against T cell-mediated ANG II hypertension is eliminated once females enter menopause, suggesting that a change in hormonal status upregulates macrophage-induced proinflammatory and T cell-dependent responses. Furthermore, we are the first to report that the presence of Tregs are required to suppress ANG II hypertension in premenopausal females. Whether progression into menopause eliminated female protection against T cell-mediated hypertension was examined. Menopausal mice without T cells remained protected against angiotensin II (ANG II) hypertension; however, in the presence of T cells, blood pressure responses to ANG II increased significantly in menopause. Underlying mechanisms examined were anti-inflammatory protection provided by T regulatory cells in premenopausal females and renal inflammatory processes involving macrophage infiltration and cytokine activation.
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http://dx.doi.org/10.1152/ajpheart.00792.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732479PMC
August 2019

Do cytomegalovirus-specific memory T cells interfere with new immune responses in lymphoid tissues?

Geroscience 2019 04 8;41(2):155-163. Epub 2019 May 8.

Department of Immunobiology and the University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, P.O. Box 221245, 1501 N Campbell Ave, Tucson, AZ, 85724, USA.

In both mice and humans, the CD8 T cell compartment is expanded with age in the presence of a cytomegalovirus (CMV) infection due to an absolute increase in the CD8+ T cell effector memory (T) cells. It has been hypothesized that in CMV+ subjects, such accumulated T cells could interfere with responses to new infection by competing for space/resources or could inhibit new responses by other, undefined, means. Here we present evidence against this hypothesis. We show that MCMV-specific CD8 T cells accumulate in blood and bone marrow, but not lymph nodes (frequent sites of immune response initiation), in either persistent lifelong CMV infection or following reactivation. Moreover, adoptive transfer of effector memory T cells from MCMV positive mice into naïve animals did not interfere with either humoral or cellular response to West Nile virus or Listeria monocytogenes infection in recipient mice. We conclude that MCMV infection is unlikely to inhibit new immune responses in old animals through direct interference of MCMV-specific CD8 T cells with the priming.
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http://dx.doi.org/10.1007/s11357-019-00068-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544713PMC
April 2019

Impact of CMV upon immune aging: facts and fiction.

Med Microbiol Immunol 2019 Aug 19;208(3-4):263-269. Epub 2019 Apr 19.

Department of Immunobiology and the University of Arizona Center on Aging, University of Arizona College of Medicine-Tucson, Tucson, AZ, 85718, USA.

Aging is accompanied by significant defects in immunity and compromised responses to new, previously unencountered microbial pathogens. Most humans carry several persistent or latent viruses as they age, interacting with the host immune systems for years. In that context maybe the most studied persistent virus is Cytomegalovirus, infamous for its ability to recruit very large T cell responses which increase with age and to simultaneously evade elimination by the immune system. Here we will address how lifelong CMV infection and the immunological burden of its control might affect immune reactivity and health of the host over time.
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http://dx.doi.org/10.1007/s00430-019-00605-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635032PMC
August 2019

Frailty as a prognostic factor for the critically ill older adult trauma patients.

Am J Surg 2019 09 22;218(3):484-489. Epub 2019 Feb 22.

Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, AZ, United States. Electronic address:

Background: Frailty is highly prevalent in the elderly and confers high risk for adverse outcomes. We aimed to assess the impact of frailty on critically ill older adult trauma patients.

Methods: We analyzed the ACS-TQIP(2010-2014) including all critically-ill trauma patients ≥65y. The modified frailty index (mFI) was calculated. Following stratified into frail and non-frail, propensity score matching was performed. Our primary outcome measure was in-hospital complications. Secondary outcome measures included mortality and discharge disposition.

Results: We identified 88,629 patients, of which 34,854 patients (frail: 17,427, non-frail: 17,427) were matched. Overall 14% died. Frail patients had higher rates of complications (34% vs. 18%, p < 0.001), mortality (18.1% vs. 9.7%, p < 0.001), and were more likely to be discharged to rehab/SNF (58.7% vs. 21.2% p < 0.001) compared to non-frail patients.

Conclusion: critically-ill frail patients are more likely to have higher morbidity and mortality. Frailty can be used as an objective measure to identify high-risk patients.
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http://dx.doi.org/10.1016/j.amjsurg.2019.01.035DOI Listing
September 2019

The acute inflammatory response after trauma is heightened by frailty: A prospective evaluation of inflammatory and endocrine system alterations in frailty.

J Trauma Acute Care Surg 2019 Jul;87(1):54-60

From the Division of Trauma, Critical Care, Emergency Surgery, and Burns, Department of Surgery (J.P., V.P., M.Z., N.K., M.H., K.H., E-R.Z., B.J.), College of Medicine, Section of Geriatrics, General Internal Medicine and Palliative Medicine (M.F.), and Department of Immunobiology College of Medicine (J.N-Z.), University of Arizona, Tucson, Arizona.

Background: Frailty is a geriatric syndrome characterized by decreased physiological reserves, increased inflammation, and decreased anabolic-endocrine response. The biomarkers associated with frailty are poorly understood in trauma. The aim of this study was to analyze the association between frailty and immune: IL-1β, IL-6, IL-2Rα, tumor necrosis factor (TNF)-α, and endocrine biomarkers: insulin-like growth factor-1 and growth hormone in trauma patients.

Methods: We conducted a 1-year (2017-2018) prospective analysis of geriatric (≥65 years) trauma patients admitted to our Level I trauma center. Frailty was measured using the trauma-specific frailty index (TSFI) and blood samples were collected within 24 hours of admission. Patients were stratified into two groups: frail (TSFI > 0.25) and nonfrail (TSFI ≤ 0.25). We then measured the levels of immune and endocrine biomarkers by a colorimetric output that was read by a spectrophotometer (Quantikine ELISA). The outcome measures were the levels of the immune and endocrine markers in the two groups. Multivariable linear regression was performed.

Results: A total of 100 geriatric trauma patients were consented and enrolled. The mean age was 77.1 ± 9.8 years and 34% were female. Thirty-nine (39%) patients were frail. Frail patients were more likely to present after falls (p = 0.01). There was no difference in age (p = 0.78), sex (p = 0.77), systolic blood pressure (p = 0.16), and heart rate (p = 0.24) between the two groups. Frail patients had higher levels of TNF-α (p = 0.01), IL-1β (p = 0.01), and IL-6(p = 0.01) but lower levels of growth hormone (p = 0.03) and insulin-like growth factor-1 (p < 0.04) compared with nonfrail patients. There was no difference in the level of IL-2Rα (p = 0.25). On regression analysis, frailty was positively correlated with the levels of proinflammatory biomarkers, that is, TNF- α, IL-1 β, and IL-6 and negatively correlated with endocrine biomarkers.

Conclusion: This study supports the association between frailty and immune and endocrine markers. Frailty acts synergistically with trauma in increasing the acute inflammatory response. Moreover, frail patients have lower levels of anabolic hormones. Understanding the inflammatory and endocrine response in frail trauma patients may result in better therapeutic strategies.
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http://dx.doi.org/10.1097/TA.0000000000002229DOI Listing
July 2019

Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates.

Aging Cell 2019 02 14;18(1):e12865. Epub 2018 Nov 14.

Department of Immunobiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona.

In youth, thymic involution curtails production of new naïve T cells, placing the onus of T-cell maintenance upon secondary lymphoid organs (SLO). This peripheral maintenance preserves the size of the T-cell pool for much of the lifespan, but wanes in the last third of life, leading to a dearth of naïve T cells in blood and SLO, and contributing to suboptimal immune defense. Both keratinocyte growth factor (KGF) and sex steroid ablation (SSA) have been shown to transiently increase the size and cellularity of the old thymus. It is less clear whether this increase can improve protection of old animals from infectious challenge. Here, we directly measured the extent to which thymic rejuvenation benefits the peripheral T-cell compartment of old mice and nonhuman primates. Following treatment of old animals with either KGF or SSA, we observed robust rejuvenation of thymic size and cellularity, and, in a reporter mouse model, an increase in recent thymic emigrants (RTE) in the blood. However, few RTE were found in the spleen and even fewer in the lymph nodes, and SSA-treated mice showed no improvement in immune defense against West Nile virus. In parallel, we found increased disorganization and fibrosis in old LN of both mice and nonhuman primates. These results suggest that SLO defects with aging can negate the effects of successful thymic rejuvenation in immune defense.
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http://dx.doi.org/10.1111/acel.12865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351843PMC
February 2019

Prospective evaluation of frailty and functional independence in older adult trauma patients.

Am J Surg 2018 12 16;216(6):1070-1075. Epub 2018 Oct 16.

Division of Trauma, Critical Care, Emergency Surgery and Burns, Department of Surgery, College of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address:

Background: The aim of our study was to assess the association between frailty and functional status in geriatric trauma patients.

Methods: 3-year(2013-2015) prospective analysis and included all geriatric trauma patients(≥65y) discharged to a single rehabilitation center from our level-I trauma center. Frailty was measured using Trauma-Specific-Frailty-Index(TSFI) while Functional status was assessed using functional-independence-measure(FIM) at admission and discharge from rehabilitation center. Multivariate linear regression analysis was performed.

Results: 267 patients were enrolled. Mean age was 76.9 ± 7.1y, 63.6% were males. Overall, 22.8% were frail, and 37.4% were pre-frail. On linear regression, higher motor-FIM, higher cognitive-FIM scores at admission, and longer length-of-stay at rehab were independently associated with increased discharge FIM score. While, ISS(injury-severity-score), pre-frail and frail status were negatively correlated with FIM gain.

Conclusion: Frail patients were less likely to recover to their baseline functional status compared with non-frail patients. Early focused intervention in frail elderly patients is warranted to improve functional status in this population.
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http://dx.doi.org/10.1016/j.amjsurg.2018.10.023DOI Listing
December 2018

Impact of early life exposure to ionizing radiation on influenza vaccine response in an elderly Japanese cohort.

Vaccine 2018 10 28;36(45):6650-6659. Epub 2018 Sep 28.

Department of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan.

The objective of this study was to evaluate effects of whole body radiation exposure early in life on influenza vaccination immune responses much later in life. A total of 292 volunteers recruited from the cohort members of ongoing Adult Health Study (AHS) of Japanese atomic bomb (A-bomb) survivors completed this observational study spanning two influenza seasons (2011-2012 and 2012-2013). Peripheral blood samples were collected prior to and three weeks after vaccination. Serum hemagglutination inhibition (HAI) antibody titers were measured as well as concentrations of 25 cytokines and chemokines in culture supernatant from peripheral blood mononuclear cells, with and without in vitro stimulation with influenza vaccine. We found that influenza vaccination modestly enhanced serum HAI titers in this unique cohort of elderly subjects, with seroprotection ranging from 18 to 48% for specific antigen/season combinations. Twelve percent of subjects were seroprotected against all three vaccine antigens post-vaccination. Males were generally more likely to be seroprotected for one or more antigens post-vaccination, with no differences in vaccine responses based on age at vaccination or radiation exposure in early life. These results show that early life exposure to ionizing radiation does not prevent responses of elderly A-bomb survivors to seasonal influenza vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2018.09.054DOI Listing
October 2018

Author Correction: The twilight of immunity: emerging concepts in aging of the immune system.

Nat Immunol 2018 Oct;19(10):1146

Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine-Tucson, Tucson, AZ, USA.

In the version of this Review initially published, the type of cell in the final sentence of the legend to Figure 3 (group 2 innate lymphoid cells) was incorrect. The correct type of cell is group 3 innate lymphoid cells. The error has been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41590-018-0205-0DOI Listing
October 2018

Lifelong CMV infection improves immune defense in old mice by broadening the mobilized TCR repertoire against third-party infection.

Proc Natl Acad Sci U S A 2018 07 2;115(29):E6817-E6825. Epub 2018 Jul 2.

Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724;

Lifelong interactions between host and the ubiquitous and persistent cytomegalovirus (CMV) have been proposed to contribute to the age-related decline in immunity. Prior work from us and others found some support for that idea, yet evidence that this led to increased vulnerability to other infections was not obtained. Moreover, evidence has accumulated that CMV infection can be beneficial to immune defense in young/adult mice and humans, dominantly via enhanced innate immunity. Here, we describe an unexpected impact of murine CMV (MCMV) upon the T cell response of old mice to expressing the model antigen, OVA (Lm-OVA). Single-cell sequencing of the OVA-specific CD8 T cell receptor β (TCRβ) repertoire of old mice demonstrated that old MCMV-infected mice recruited many diverse clonotypes that afforded broad and often more efficient recognition of antigenic peptide variants. This stood in contrast to old control mice, which exhibited strong narrowing and homogenization of the elicited repertoire. High-throughput sequencing of the total naïve CD8 TCRβ repertoire showed that many of these diverse OVA-specific clonotypes were present in the naïve CD8 repertoire of mice in all groups (adult, old control, and old MCMV) yet were only recruited into the Lm-OVA response in MCMV old mice. These results have profound implications for our understanding of T cell immunity over a life span and suggest that our coevolution with CMV may include surprising, potentially positive impacts on adaptive heterologous immunity in late life.
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http://dx.doi.org/10.1073/pnas.1719451115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055168PMC
July 2018

A disconnect between precursor frequency, expansion potential, and site-specific CD4+ T cell responses in aged mice.

PLoS One 2018 4;13(6):e0198354. Epub 2018 Jun 4.

Department of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ, United States of America.

T cell recognition of peptides presented within self-major histocompatibility complex (pMHC) molecules is essential for long-lived protective immunity. As mice age the number of naïve CD4+ and CD8+ T cells declines. However, unlike for CD8+ T cells, there are more naïve and memory phenotype CD4+ T cells that bind foreign pMHCII in old mice (18-22 months) than adults (12-15 weeks), suggesting increased promiscuity of pMHCII recognition with aging. Here we asked if CD4+ T cell responses to immunization or infection increase with aging since the magnitude of a CD4+ T cell response to a foreign pMHCII is proportional to the size of the precursor population in adult mice. We observed no difference in the number of pMHCII-specific CD4+ T cells in adult versus old mice for pooled secondary lymphoid organs after immunization, bacterial infection, or viral infection, but we did observe diminished numbers of pMHCII-specific CD4+ T cells in both the draining lymph node and brain of old mice after West Nile virus infection. These data indicate that an increased precursor frequency does not translate into more robust responses upon immunization or infection in old mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198354PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986155PMC
December 2018

Calorie restriction induces reversible lymphopenia and lymphoid organ atrophy due to cell redistribution.

Geroscience 2018 06 26;40(3):279-291. Epub 2018 May 26.

Department of Immunobiology, College of Medicine, The University of Arizona, Tucson, AZ, USA.

Calorie restriction (CR) without malnutrition increases life span and health span in multiple model organisms. In non-human and human primates, CR causes changes that protect against several age-related pathologies, reduces inflammation, and preserves or improves cell-mediated immunity. However, CR has also been shown to exhibit adverse effects on certain organs and systems, including the immune system, and to impact genetically different organisms of the same species differentially. Alternately, short periods of fasting followed by refeeding may result in the proliferation of bone marrow stem cells, suggesting a potential rejuvenation effect that could impact the hematopoietic compartment. However, the global consequences of CR followed by refeeding on the immune system have not been carefully investigated. Here, we show that individuals practicing long-term CR with adequate nutrition have markedly lower circulating levels of total leukocytes, neutrophils, lymphocytes, and monocytes. In 10-month-old mice, short-term CR lowered lymphocyte cellularity in multiple lymphoid tissues, but not in bone marrow, which appears to be a site of influx, or a "safe haven" for B, NK, and T cells during CR. Cellular loss and redistribution was reversed within the first week of refeeding. Based on BrdU incorporation and Ki67 expression assays, repopulating T cells exhibited high proliferation in the refeeding group following CR. Finally, we demonstrated that the thymus was not essential for T cell repopulation following refeeding. These findings are of potential relevance to strategies to rejuvenate the immune system in mammals and warrant further investigation.
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http://dx.doi.org/10.1007/s11357-018-0022-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060198PMC
June 2018

The Contribution of Cytomegalovirus Infection to Immune Senescence Is Set by the Infectious Dose.

Front Immunol 2017 10;8:1953. Epub 2018 Jan 10.

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands.

The relationship between human cytomegalovirus (HCMV) infections and accelerated immune senescence is controversial. Whereas some studies reported a CMV-associated impaired capacity to control heterologous infections at old age, other studies could not confirm this. We hypothesized that these discrepancies might relate to the variability in the infectious dose of CMV occurring in real life. Here, we investigated the influence of persistent CMV infection on immune perturbations and specifically addressed the role of the infectious dose on the contribution of CMV to accelerated immune senescence. We show in experimental mouse models that the degree of mouse CMV (MCMV)-specific memory CD8 T cell accumulation and the phenotypic T cell profile are directly influenced by the infectious dose, and data on HCMV-specific T cells indicate a similar connection. Detailed cluster analysis of the memory CD8 T cell development showed that high-dose infection causes a differentiation pathway that progresses faster throughout the life span of the host, suggesting a virus-host balance that is influenced by aging and infectious dose. Importantly, short-term MCMV infection in adult mice is not disadvantageous for heterologous superinfection with lymphocytic choriomeningitis virus (LCMV). However, following long-term CMV infection the strength of the CD8 T cell immunity to LCMV superinfection was affected by the initial CMV infectious dose, wherein a high infectious dose was found to be a prerequisite for impaired heterologous immunity. Altogether our results underscore the importance of stratification based on the size and differentiation of the CMV-specific memory T cell pools for the impact on immune senescence, and indicate that reduction of the latent/lytic viral load can be beneficial to diminish CMV-associated immune senescence.
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http://dx.doi.org/10.3389/fimmu.2017.01953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768196PMC
January 2018

Intrinsic and extrinsic contributors to defective CD8+ T cell responses with aging.

Exp Gerontol 2018 05 11;105:140-145. Epub 2018 Jan 11.

Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724, United States. Electronic address:

Aging has a profound effect on the immune system, and both innate and adaptive arms of the immune system show functional decline with age. In response to infection with intracellular microorganisms, old animals mobilize decreased numbers of antigen-specific CD8+ T cells with reduced production of effector molecules and impaired cytolytic activity. However, the CD8+ T cell-intrinsic contribution to, and molecular mechanisms behind, these defects remain unclear. In this review we will discuss the mechanistic contributions of age related changes in the CD8+ T cell pool and the relative roles of intrinsic functional defects in aged CD8+ T cells vs. defects in the aged environment initiating the CD8+ T cell response.
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http://dx.doi.org/10.1016/j.exger.2018.01.011DOI Listing
May 2018

The twilight of immunity: emerging concepts in aging of the immune system.

Nat Immunol 2018 Jan 14;19(1):10-19. Epub 2017 Dec 14.

Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine-Tucson, Tucson, AZ, USA.

Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age-related changes in immunity might also affect the basic rules by which the immune system operates.
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http://dx.doi.org/10.1038/s41590-017-0006-xDOI Listing
January 2018