Anne M Wertheimer
- Assistant Research Professor
- Assistant Professor, Applied BioSciences - GIDP
- Immunization Champions and Mentors Program
- Gerontological Society of America, Fall 2015
- Butler Williams Summer NIA Program
- National Institute on Aging, Summer 2015
No activities entered.
Internship in Applied BiosciABS 593A (Fall 2016)
Master's ReportABS 909 (Fall 2016)
Internship in Applied BiosciABS 593A (Summer I 2016)
Master's ReportABS 909 (Summer I 2016)
Internship in Applied BiosciABS 593A (Spring 2016)
Master's ReportABS 909 (Spring 2016)
- Nikolich-Žugich, J., Goldman, D. P., Cohen, P. R., Cortese, D., Fontana, L., Kennedy, B. K., Mohler, M. J., Olshansky, S. J., Perls, T., Perry, D., Richardson, A., Ritchie, C., Wertheimer, A. M., Faragher, R. G., & Fain, M. J. (2016). Preparing for an Aging World: Engaging Biogerontologists, Geriatricians, and the Society. The journals of gerontology. Series A, Biological sciences and medical sciences, 71(4), 435-44.More infoAlthough the demographic revolution has produced hundreds of millions people aged 65 and older, a substantial segment of that population is not enjoying the benefits of extended healthspan. Many live with multiple chronic conditions and disabilities that erode the quality of life. The consequences are also costly for society. In the United States, the most costly 5% of Medicare beneficiaries account for approximately 50% of Medicare's expenditures. This perspective summarizes a recent workshop on biomedical approaches to best extend healthspan as way to reduce age-related dysfunction and disability. We further specify the action items necessary to unite health professionals, scientists, and the society to partner around the exciting and palpable opportunities to extend healthspan.
- Pulko, V., Davies, J. S., Martinez, C., Lanteri, M. C., Busch, M. P., Diamond, M. S., Knox, K., Bush, E. C., Sims, P. A., Sinari, S., Billheimer, D., Haddad, E. K., Murray, K. O., Wertheimer, A. M., & Nikolich-Žugich, J. (2016). Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nature immunology, 17(8), 966-75.More infoThe number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens.
- Metcalf, T. U., Cubas, R. A., Ghneim, K., Cartwright, M. J., Grevenynghe, J. V., Richner, J. M., Olagnier, D. P., Wilkinson, P. A., Cameron, M. J., Park, B. S., Hiscott, J. B., Diamond, M. S., Wertheimer, A. M., Nikolich-Zugich, J., & Haddad, E. K. (2015). Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging cell, 14(3), 421-32.More infoAging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells (PBMCs), we first undertook transcriptional profiling and found that PBMCs isolated from old individuals (≥ 65 years) exhibited a delayed and altered response to stimulation with TLR4, TLR7/8, and RIG-I agonists compared to cells obtained from adults (≤ 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro-inflammatory and antiviral cytokines and chemokines including TNFα, IL-6, IL-1β, IFNα, IFNγ, CCL2, and CCL7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMCs from old subjects also had a lower frequency of CD40+ monocytes, impaired up-regulation of PD-L1 on monocytes and T cells, and increased expression of PD-L2 and B7-H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR-stimulated PBMCs (minus CD3 T cells) from old subjects elicited significantly lower levels of adult T-cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction (MLR). Collectively, these age-associated changes in cytokine, chemokine and interferon production, as well as co-stimulatory protein expression could contribute to the blunted memory B- and T-cell immune responses to vaccines and infections.
- Mohler, M. J., Fain, M. J., Wertheimer, A. M., Najafi, B., & Nikolich-Žugich, J. (2014). The Frailty syndrome: clinical measurements and basic underpinnings in humans and animals. Experimental gerontology, 54, 6-13.More infoFrailty is an increasingly recognized syndrome resulting in age-related decline in function and reserve across multiple physiologic systems. It presents as a hyperinflammable state, characterized by high vulnerability for adverse health outcomes, such as disability, falls, hospitalization, institutionalization, and mortality. The prevalence of Frailty Syndrome (FS) is of potentially enormous significance, as it potentially affects 20-30% of adults older than 75. Cellular and molecular basis of frailty has not been elucidated. The objective of this review is to discuss recent advances in: (i) the potential cellular and molecular basis of Frailty Syndrome, including development of new models to study it; (ii) the human and animal measures of Frailty Syndrome; and (iii) the development of objective cross-species correlates to aid the basic understanding, diagnosis, treatment and rehabilitation of Frailty Syndrome in older adults.
- Griffiths, S. J., Riddell, N. E., Masters, J., Libri, V., Henson, S. M., Wertheimer, A., Wallace, D., Sims, S., Rivino, L., Larbi, A., Kemeny, D. M., Nikolich-Zugich, J., Kern, F., Klenerman, P., Emery, V. C., & Akbar, A. N. (2013). Age-associated increase of low-avidity cytomegalovirus-specific CD8+ T cells that re-express CD45RA. Journal of immunology (Baltimore, Md. : 1950), 190(11), 5363-72.More infoThe mechanisms regulating memory CD8(+) T cell function and homeostasis during aging are unclear. CD8(+) effector memory T cells that re-express CD45RA increase considerably in older humans and both aging and persistent CMV infection are independent factors in this process. We used MHC class I tetrameric complexes that were mutated in the CD8 binding domain to identify CMV-specific CD8(+) T cells with high Ag-binding avidity. In individuals who were HLA-A*0201, CD8(+) T cells that expressed CD45RA and were specific for the pp65 protein (NLVPMVATV epitope) had lower avidity than those that expressed CD45RO and demonstrated decreased cytokine secretion and cytolytic potential after specific activation. Furthermore, low avidity NLVPMVATV-specific CD8(+) T cells were significantly increased in older individuals. The stimulation of blood leukocytes with CMV lysate induced high levels of IFN-α that in turn induced IL-15 production. Moreover, the addition of IL-15 to CD45RA(-)CD45RO(+) CMV-specific CD8(+) T cells induced CD45RA expression while Ag activated cells remained CD45RO(+). This raises the possibility that non-specific cytokine-driven accumulation of CMV-specific CD8(+)CD45RA(+) T cells with lower Ag-binding avidity may exacerbate the effects of viral reactivation on skewing the T cell repertoire in CMV-infected individuals during aging.
- Wertheimer, A. M., Uhrlaub, J. L., Hirsch, A., Medigeshi, G., Sprague, J., Legasse, A., Wilk, J., Wiley, C. A., Didier, P., Tesh, R. B., Murray, K. O., Axthelm, M. K., Wong, S. W., & Nikolich-Žugich, J. (2010). Immune response to the West Nile virus in aged non-human primates. PloS one, 5(12), e15514.More infoRisk of encephalitis from West Nile virus (WNV) infection increases dramatically with age. Understanding the basis of this susceptibility requires development of suitable animal models. Here, we investigated the immune response to WNV in old non-human primates.
- Wertheimer, A. M., Polyak, S. J., Leistikow, R., & Rosen, H. R. (2007). Engulfment of apoptotic cells expressing HCV proteins leads to differential chemokine expression and STAT signaling in human dendritic cells. Hepatology (Baltimore, Md.), 45(6), 1422-32.More infoIn the majority of cases, infection with hepatitis C virus (HCV) becomes chronic and is often associated with impaired innate and adaptive immune responses. The mechanisms underlying viral persistence and lack of protective immunity are poorly understood. Considering that dendritic cells (DCs) play critical roles in initiating and modulating immune responses, we explored the effect of HCV proteins on DC gene and protein expression, phenotype, and function. Human DCs were generated following plastic adherence of monocytes and culture with granulocyte-macrophage colony-stimulating factor and interleukin-4 (IL-4) from normal subjects. Autologous nonadherent peripheral blood mononuclear cells were infected with vaccinia constructs expressing various HCV proteins (core-E1, NS5A, NS5B) or an irrelevant protein beta-galactosidase (beta-gal) as the control, induced to undergo apoptosis, then co-cultured with DCs. Between 2% and 10% of the genes probed in a cDNA nylon array were differentially regulated within DCs that had engulfed HCV proteins. In particular, the presence of intracellular NS5A led to increased transcriptional and protein expression of IL-8 (CXCL-8), a chemokine with proinflammatory and anti-interferon properties, and impaired interferon induction of signal transducers and activators of transcription 1 (STAT1) serine and tyrosine and STAT2 tyrosine phosphorylation.
- Wertheimer, A. M., Bakke, A., & Rosen, H. R. (2004). Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology (Baltimore, Md.), 40(2), 335-45.More infoChronic liver disease has been shown to be associated with diminished humoral and cellular immune function. Although antigen-presenting cells (APC) that initiate immune responses include various cells (B cells, endothelial cells, macrophages, etc.), the dendritic cell (DC) is a professional APC that activates naive T cells most efficiently. To examine the frequency and function of DCs in chronic liver disease, we studied circulating DCs from a cohort of 112 subjects (23 normal subjects, 29 subjects who had spontaneously recovered from hepatitis C virus [HCV] infection, 30 chronically infected HCV patients, and 30 patients with liver disease unrelated to HCV infection). Our analyses revealed significant reduction in both circulating myeloid (mDC) and plasmacytoid dendritic cells (pDC) in patients with liver disease. In contrast, examination of subjects with spontaneously resolved HCV infection revealed no significant difference in either circulating mDCs or pDCs. We found an inverse correlation with serum alanine aminotransferase (ALT) levels and both mDCs and pDCs frequency. In a subset of patients for whom intrahepatic cells were available, paired analysis revealed enrichment for DCs within the intrahepatic compartment. Interferon alfa (IFN-alpha) production in response to influenza A and poly (I:C) correlated with the frequency of circulating DCs, although IFN-alpha production was comparable on a per-DC basis in patients with liver disease. In conclusion, patients with liver disease exhibit a reduction in circulating DCs. Considering that DCs are essential for initiation and regulation of innate and adaptive immunity, these findings have implications for both viral persistence and liver disease.
- Di Lorenzo, M., Stork, M., Tolmasky, M. E., Actis, L. A., Farrell, D., Welch, T. J., Crosa, L. M., Wertheimer, A. M., Chen, Q., Salinas, P., Waldbeser, L., & Crosa, J. H. (2003). Complete sequence of virulence plasmid pJM1 from the marine fish pathogen Vibrio anguillarum strain 775. Journal of bacteriology, 185(19), 5822-30.More infoThe virulence plasmid pJM1 enables the fish pathogen Vibrio anguillarum, a gram-negative polarly flagellated comma-shaped rod bacterium, to cause a highly fatal hemorrhagic septicemic disease in salmonids and other fishes, leading to epizootics throughout the world. The pJM1 plasmid 65,009-nucleotide sequence, with an overall G+C content of 42.6%, revealed genes and open reading frames (ORFs) encoding iron transporters, nonribosomal peptide enzymes, and other proteins essential for the biosynthesis of the siderophore anguibactin. Of the 59 ORFs, approximately 32% were related to iron metabolic functions. The plasmid pJM1 confers on V. anguillarum the ability to take up ferric iron as a complex with anguibactin from a medium in which iron is chelated by transferrin, ethylenediamine-di(o-hydroxyphenyl-acetic acid), or other iron-chelating compounds. The fatDCBA-angRT operon as well as other downstream biosynthetic genes is bracketed by the homologous ISV-A1 and ISV-A2 insertion sequences. Other clusters on the plasmid also show an insertion element-flanked organization, including ORFs homologous to genes involved in the biosynthesis of 2,3-dihydroxybenzoic acid. Homologues of replication and partition genes are also identified on pJM1 adjacent to this region. ORFs with no known function represent approximately 30% of the pJM1 sequence. The insertion sequence elements in the composite transposon-like structures, corroborated by the G+C content of the pJM1 sequence, suggest a modular composition of plasmid pJM1, biased towards acquisition of modules containing genes related to iron metabolic functions. We also show that there is considerable microheterogeneity in pJM1-like plasmids from virulent strains of V. anguillarum isolated from different geographical sources.
- Wertheimer, A. M., Tolmasky, M. E., Actis, L. A., & Crosa, J. H. (1994). Structural and functional analyses of mutant Fur proteins with impaired regulatory function. Journal of bacteriology, 176(16), 5116-22.More infoVibrio anguillarum Fur mutants, 775met9 and 775met11, were characterized. V. anguillarum 775met9 had a change of D to G at position 104 located in the carboxy terminus resulting in impaired Fur activity. Computer analysis predicts perturbation of an alpha-helix in the carboxy terminus which may interfere with Fur protein conformation. Strain 775met11 had a change in the start codon resulting in no protein synthesis. The mutants are unstable, and reversion to the wild type occurs frequently.