Cavan Reilly

University of Minnesota Duluth, Duluth, Minnesota, United States

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Publications (60)379.58 Total impact

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    ABSTRACT: HIV replication causes lymphoid tissue (LT) fibrosis which causes CD4 depletion. It is unknown if people who spontaneously control HIV replication have LT fibrosis. We measured LT fibrosis and CD4 cells in 25 HIV controllers, 10 non-controllers, 45 on therapy, and 10 HIV negative individuals. Controllers had significant LT fibrosis and CD4 depletion, similar to non-controllers, but the Berlin Patient (cured of HIV) had near normal LT. Thus, LT fibrosis occurs in all HIV-infected subjects and current therapy does not reverse it. Reversal of fibrosis during a curative intervention suggests that ongoing low-level virus production may maintain LT fibrosis.
    The Journal of infectious diseases. 10/2014;
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    ABSTRACT: Cystic fibrosis (CF) patients exhibit a progressive decline in lung function accelerated by intermittent pulmonary exacerbations. There are urgent needs for clinically relevant biomarkers to aid in the diagnosis and management of a CF pulmonary exacerbation, in addition to providing insight into its pathophysiology. Club cell secretory protein (CCSP) is produced by bronchial epithelial cells, known to have anti-inflammatory properties and may play a role in CF pulmonary exacerbations. Our objective was to measure sputum CCSP concentration during hospitalizations for CF pulmonary exacerbation and during quarterly outpatient clinic visits for 2 years. We explored the correlations between CCSP concentration, lung function and markers of inflammation and infection.
    Journal of Cystic Fibrosis. 10/2014;
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    ABSTRACT: Even with prolonged antiretroviral therapy (ART), many HIV infected individuals have<500 CD4+ T cells/µL and CD4+ T cells in lymphoid tissues remain severely depleted, due in part to fibrosis of the paracortical T cell zone (TZ) that impairs homeostatic mechanisms required for T cell survival. We therefore used antifibrotic therapy in SIV infected rhesus macaques to determine if decreased TZ fibrosis would improve reconstitution of peripheral and lymphoid CD4+ T cells. Treatment with the antifibrotic drug pirfenidone preserved TZ architecture and was associated with significantly larger populations of CD4+ T cells in peripheral blood and lymphoid tissues. Combining pirfenidone with an ART regimen was associated with greater preservation of CD4+ T cells than ART alone and was also associated with higher pirfenidone concentrations. These data support a potential role for antifibrotic drug treatment as adjunctive therapy with ART to improve immune reconstitution.
    The Journal of infectious diseases. 09/2014;
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    ABSTRACT: Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic's epicenter in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer Ab production and neonatal FcR-mediated concentration of these Abs on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. In this study, we identify blocking CD4(+) T cell recruitment to thereby inhibit local expansion of infected founder populations as a second correlate of protection. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine.
    Journal of immunology (Baltimore, Md. : 1950). 08/2014;
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    ABSTRACT: We sought design principles for a vaccine to prevent HIV transmission to women by identifying correlates of protection conferred by a highly effective live attenuated SIV vaccine in the rhesus macaque animal model. We show that SIVmac239Δnef vaccination recruits plasma cells and induces ectopic lymphoid follicle formation beneath the mucosal epithelium in the rhesus macaque female reproductive tract. The plasma cells and ectopic follicles produce IgG Abs reactive with viral envelope glycoprotein gp41 trimers, and these Abs are concentrated on the path of virus entry by the neonatal FcR in cervical reserve epithelium and in vaginal epithelium. This local Ab production and delivery system correlated spatially and temporally with the maturation of local protection against high-dose pathogenic SIV vaginal challenge. Thus, designing vaccines to elicit production and concentration of Abs at mucosal frontlines could aid in the development of an effective vaccine to protect women against HIV-1.
    Journal of immunology (Baltimore, Md. : 1950). 08/2014;
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    ABSTRACT: Alternative polyadenylation (APA) is an evolutionarily conserved mechanism for regulating gene expression. Transcript 3' end shortening through changes in polyadenylation site usage occurs following T cell activation, but the consequences of APA on gene expression are poorly understood. We previously showed that GU-rich elements (GREs) found in the 3' untranslated regions of select transcripts mediate rapid mRNA decay by recruiting the protein CELF1/CUGBP1. Using a global RNA sequencing approach, we found that a network of CELF1 target transcripts involved in cell division underwent preferential 3' end shortening via APA following T cell activation, resulting in decreased inclusion of CELF1 binding sites and increased transcript expression. We present a model whereby CELF1 regulates APA site selection following T cell activation through reversible binding to nearby GRE sequences. These findings provide insight into the role of APA in controlling cellular proliferation during biological processes such as development, oncogenesis and T cell activation.
    Gene 08/2014; · 2.20 Impact Factor
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    ABSTRACT: Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution.
    Proceedings of the National Academy of Sciences 01/2014; · 9.81 Impact Factor
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    ABSTRACT: Live-attenuated SIV vaccines (LAVs) have been the most effective to date in preventing or partially controlling infection by wild-type SIV in non-human primate models of HIV-1 transmission to women acting by mechanisms of protection that are not well understood. To gain insights into mechanisms of protection by LAVs that could aid development of effective vaccines to prevent HIV-1 transmission to women, we used in situ tetramer staining to determine whether increased densities or changes in the local distribution of SIV-specific CD8 T cells correlated with the maturation of SIVΔnef vaccine-induced protection prior to and after intra-vaginal challenge with wild-type SIVmac251. We evaluated the immunodominant Mamu-A1*001:01/Gag (CM9) and Mamu-A1*001:01/Tat (SL8) epitope response in genital and lymphoid tissues, and found that tetramer+ cells were present at all time points examined. In the cervical vaginal tissues, most tetramer+ cells were distributed diffusely throughout the lamina propria or co-localized with other CD8 T cells within lymphoid aggregates. The distribution and densities of the tetramer+ cells at the portal of entry did not correlate with the maturation of protection or change after challenge. Given these findings, we discuss the possibility that changes in other aspects of the immune system, including the quality of the resident population of virus-specific effector CD8 T cells could contribute to maturation of protection, as well as the potential for vaccine strategies that further increase the size and quality of this effector population to prevent HIV-1 transmission.
    PLoS ONE 01/2013; 8(12):e81623. · 3.53 Impact Factor
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    ABSTRACT: Background: Management goals for HIV are shifting from chronic viral suppression to functional cure; i.e. control of HIV in the absence of combination antiretroviral therapy (cART). Assessment of such novel treatments will require interruption of standard cART, yet structured treatment interruptions (STIs) have generally been avoided given safety concerns. This study was designed to assess the safety, as determined by resumption of virologic control after treatment re-initiation, maintenance of CD4 T cell count, and lack of clinical adverse events, of a short-term STI in patients with preserved CD4 T cell count and virologic suppression on cART. Methods: 14 HIV-infected individuals with CD4 count >350 cells/mm3 and virologic suppression on cART were enrolled in an STI treatment protocol designed to characterize HIV reservoirs. All subjects underwent interruption of cART at study initiation. Peripheral blood CD4 count and HIV viral load were assessed 3 times weekly while off of cART. Once HIV RNA was detected in peripheral blood, samples for the reservoir study were collected, genotype was obtained and cART was restarted. CD4 count and HIV viral load were followed weekly until viral load was undetectable then intermittently for up to 90 days. Results: After cART discontinuation, median time to HIV viremia was 14 days (range 5-29). At cART re-initiation, median viral load was 871 copies/mL (60-23,402 copies/mL). Longer duration of HIV infection and lower reported CD4 nadir were associated with more rapid virologic rebound (p=0.019 and 0.016). Longer lifetime exposure to ART was associated with more prolonged time to viremia (p=0.029). Once cART was restarted, all subjects achieved peripheral blood viral suppression, with median time to suppression being 14 days (7-47). CD4 count at treatment resumption did not differ from study initiation (p=0.18), no new resistance-conferring mutations were detected in any subject and none had symptoms associated with reactivation of viral replication. No subjects developed virologic failure during post-STI follow up period. Conclusion: Brief interruption of cART in patients with preserved CD4 count and virologic suppression is safe for the evaluation of novel therapies to test for cure of HIV.
    IDWeek 2012 Meeting of the Infectious Diseases Society of America; 10/2012
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by incompletely reversible airflow obstruction. Bacterial infection of the lower respiratory tract contributes to approximately 50% of COPD exacerbations. Even during periods of stable lung function, the lung harbors a community of bacteria, termed the microbiome. The role of the lung microbiome in the pathogenesis of COPD remains unknown. The COPD lung microbiome, like the healthy lung microbiome, appears to reflect microaspiration of oral microflora. Here we describe the COPD lung microbiome of 22 patients with Moderate or Severe COPD compared to 10 healthy control patients. The composition of the lung microbiomes was determined using 454 pyrosequencing of 16S rDNA found in bronchoalveolar lavage fluid. Sequences were analyzed using mothur, Ribosomal Database Project, Fast UniFrac, and Metastats. Our results showed a significant increase in microbial diversity with the development of COPD. The main phyla in all samples were Actinobacteria, Firmicutes, and Proteobacteria. Principal coordinate analyses demonstrated separation of control and COPD samples, but samples did not cluster based on disease severity. However, samples did cluster based on the use of inhaled corticosteroids and inhaled bronchodilators. Metastats analyses demonstrated an increased abundance of several oral bacteria in COPD samples.
    PLoS ONE 10/2012; 7(10):e47305. · 3.53 Impact Factor
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    Retrovirology 09/2012; 9(2). · 5.66 Impact Factor
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    ABSTRACT: Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication and normalize the chronic immune activation associated with infection, but restoration of naïve CD4+ T cell populations is slow and usually incomplete for reasons that have yet to be determined. We tested the hypothesis that damage to the lymphoid tissue (LT) fibroblastic reticular cell (FRC) network contributes to naïve T cell loss in HIV-1 infection by restricting access to critical factors required for T cell survival. We show that collagen deposition and progressive loss of the FRC network in LTs prior to treatment restrict both access to and a major source of the survival factor interleukin-7 (IL-7). As a consequence, apoptosis within naïve T cell populations increases significantly, resulting in progressive depletion of both naïve CD4+ and CD8+ T cell populations. We further show that the extent of loss of the FRC network and collagen deposition predict the extent of restoration of the naïve T cell population after 6 month of HAART, and that restoration of FRC networks correlates with the stage of disease at which the therapy is initiated. Because restoration of the FRC network and reconstitution of naïve T cell populations are only optimal when therapy is initiated in the early/acute stage of infection, our findings strongly suggest that HAART should be initiated as soon as possible. Moreover, our findings also point to the potential use of adjunctive anti-fibrotic therapies to avert or moderate the pathological consequences of LT fibrosis, thereby improving immune reconstitution.
    PLoS Pathogens 01/2012; 8(1):e1002437. · 8.14 Impact Factor
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    ABSTRACT: One pathological hallmark of HIV-1 infection is chronic activation of the immune system, driven, in part, by increased expression of proinflammatory cytokines. The host attempts to counterbalance this prolonged immune activation through compensatory mediators of immune suppression. We recently identified a gene encoding the proinflammatory cytokine IL-32 in microarray studies of HIV-1 infection in lymphatic tissue (LT) and show in this study that increased expression of IL-32 in both gut and LT of HIV-1-infected individuals may have a heretofore unappreciated role as a mediator of immune suppression. We show that: 1) IL-32 expression is increased in CD4(+) T cells, B cells, macrophages, dendritic cells, and epithelial cells in vivo; 2) IL-32 induces the expression of immunosuppressive molecules IDO and Ig-like transcript 4 in immune cells in vitro; and 3) in vivo, IL-32-associated IDO/Ig-like transcript 4 expression in LT macrophages and gut epithelial cells decreases immune activation but also may impair host defenses, supporting productive viral replication, thereby accounting for the correlation between IL-32 levels and HIV-1 replication in LT. Thus, during HIV-1 infection, we propose that IL-32 moderates chronic immune activation to avert associated immunopathology but at the same time dampens the antiviral immune response and thus paradoxically supports HIV-1 replication and viral persistence.
    The Journal of Immunology 06/2011; 186(11):6576-84. · 5.52 Impact Factor
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    ABSTRACT: The hallmark of HIV-1 and SIV infections is CD4(+) T cell depletion. Both direct cell killing and indirect mechanisms related to immune activation have been suggested to cause the depletion of T cells. We have now identified a mechanism by which immune activation-induced fibrosis of lymphoid tissues leads to depletion of naive T cells in HIV-1 infected patients and SIV-infected rhesus macaques. The T regulatory cell response to immune activation increased procollagen production and subsequent deposition as fibrils via the TGF-β1 signaling pathway and chitinase 3-like-1 activity in fibroblasts in lymphoid tissues from patients infected with HIV-1. Collagen deposition restricted T cell access to the survival factor IL-7 on the fibroblastic reticular cell (FRC) network, resulting in apoptosis and depletion of T cells, which, in turn, removed a major source of lymphotoxin-β, a survival factor for FRCs during SIV infection in rhesus macaques. The resulting loss of FRCs and the loss of IL-7 produced by FRCs may thus perpetuate a vicious cycle of depletion of T cells and the FRC network. Because this process is cumulative, early treatment and antifibrotic therapies may offer approaches to moderate T cell depletion and improve immune reconstitution during HIV-1 infection.
    The Journal of clinical investigation 02/2011; 121(3):998-1008. · 15.39 Impact Factor
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    ABSTRACT: Microbial translocation from the gastrointestinal tract has been implicated in chronic activation of the immune system during progressive HIV-1 infection by ill-defined mechanisms. We recently identified a gene encoding syndecan-1 (SYN1) in microarray studies of HIV-1 infection in lymphatic tissues and show here that increased expression of SYN1 in the gut of HIV-1-infected individuals is associated with increased microbial translocation. We further show that: (1) microbial access to SYN1 in the intestinal epithelium could be mediated by compromised barrier function through the upregulation of claudin-2; (2) increases in SYN1 and microbial translocation are associated with systemic immune activation; and (3) SYN1 expression and microbial translocation are inversely correlated with peripheral blood CD4 T-cell counts. We thus propose a new mechanism in which claudin-2 and SYN1 work in concert to enhance microbial translocation across the intestinal epithelial barrier to contribute to chronic immune activation and CD4 T-cell depletion.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 11/2010; 55(3):306-15. · 4.65 Impact Factor
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    ABSTRACT: Much effort has been spent recently in identifying host factors required for HIV-1 to effectively replicate in cultured human cells. However, much less is known about the genetic factors in vivo that impact viral replication in lymphatic tissue, the primary anatomical site of virus-host interactions where the bulk of viral replication and pathogenesis occurs. To identify genetic determinants in lymphatic tissue that critically affect HIV-1 replication, we used microarrays to transcriptionally profile and identify host genes expressed in inguinal lymph nodes that were associated determinants of viral load. Strikingly, ∼95% of the transcripts (558) in this data set (592 transcripts total) were negatively associated with HIV-1 replication. Genes in this subset 1) inhibit cellular activation/proliferation (e.g., TCFL5, SOCS5 and SCOS7, KLF10), 2) promote heterochromatin formation (e.g., HIC2, CREBZF, ZNF148/ZBP-89), 3) increase collagen synthesis (e.g., PLOD2, POSTN, CRTAP), and 4) reduce cellular transcription and translation. Potential anti-HIV-1 restriction factors were also identified (e.g., NR3C1, HNRNPU, PACT). Only ∼5% of the transcripts (34) were positively associated with HIV-1 replication. Paradoxically, nearly all of these genes function in innate and adaptive immunity, particularly highlighting heightened gene expression in the IFN system. We conclude that this conventional host response cannot contain HIV-1 replication and, in fact, could well contribute to increased replication through immune activation. More importantly, genes that have a negative association with virus replication point to target cell availability and potentially new viral restriction factors as principal determinants of viral load.
    The Journal of Immunology 10/2010; 185(9):5417-24. · 5.52 Impact Factor
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    ABSTRACT: The functional capacity of the adaptive immune system is dependent on the size and the diversity of the T cell population. In states of lymphopenia, T cells are driven to proliferate to restore the T cell population size. However, different T cell clones proliferate at different rates, and some T cells experience burst-like expansion called spontaneous lymphopenia-induced proliferation (LIP). These T cells are likely receiving stimulation from cognate Ags and are most responsible for inflammatory pathology that can emerge in lymphopenic states. Foxp3(+) regulatory T cells (Tregs) selectively inhibit spontaneous LIP, which may contribute to their ability to prevent lymphopenia-associated autoimmunity. We hypothesized that another potential negative consequence of unrestrained spontaneous LIP is constriction of the total T cell repertoire. We demonstrate that the absence of Foxp3(+) Tregs during the period of immune reconstitution results in the development of TCR repertoire "holes" and the loss of Ag-specific responsiveness to infectious microorganisms. In contrast, the presence of Tregs during the period of immune reconstitution preserves optimal TCR diversity and foreign Ag responsiveness. This finding contrasts with the generally accepted immunosuppressive role of Tregs and provides another example of Treg activity that actually enhances immune function.
    The Journal of Immunology 03/2010; 184(9):4749-60. · 5.52 Impact Factor
  • Meijuan Li, Cavan Reilly, Tim Hanson
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    ABSTRACT: Several statistical methods for detecting associations between quantitative traits and candidate genes in structured populations have been developed for fully observed phenotypes. However, many experiments are concerned with failure-time phenotypes, which are usually subject to censoring. In this article, we propose statistical methods for detecting associations between a censored quantitative trait and candidate genes in structured populations with complex multiple levels of genetic relatedness among sampled individuals. The proposed methods correct for continuous population stratification using both population structure variables as covariates and the frailty terms attributable to kinship. The relationship between the time-at-onset data and genotypic scores at a candidate marker is modeled via a parametric Weibull frailty accelerated failure time (AFT) model as well as a semiparametric frailty AFT model, where the baseline survival function is flexibly modeled as a mixture of Polya trees centered around a family of Weibull distributions. For both parametric and semiparametric models, the frailties are modeled via an intrinsic Gaussian conditional autoregressive prior distribution with the kinship matrix being the adjacency matrix connecting subjects. Simulation studies and applications to the Arabidopsis thaliana line flowering time data sets demonstrated the advantage of the new proposals over existing approaches.
    Biometrics 11/2009; 66(3):925-33. · 1.41 Impact Factor
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    Xiaoxiao Kong, Cavan Reilly
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    ABSTRACT: The need to align spectra to correct for mass-to-charge experimental variation is a problem that arises in mass spectrometry (MS). Most of the MS-based proteomic data analysis methods involve a two-step approach, identify peaks first and then do the alignment and statistical inference on these identified peaks only. However, the peak identification step relies on prior information on the proteins of interest or a peak detection model, which are subject to error. Also numerous additional features such as peak shape and peak width are lost in simple peak detection, and these are informative for correcting mass variation in the alignment step. Here, we present a novel Bayesian approach to align the complete spectra. The approach is based on a parametric model which assumes that the spectrum and alignment function are Gaussian processes, but the alignment function is monotone. We show how to use the expectation-maximization algorithm to find the posterior mode of the set of alignment functions and the mean spectrum for a patient population. After alignment, we conduct tests while controlling for error attributable to multiple comparisons on the level of the peaks identified from the absolute mean spectra difference of two patient populations. cavanr@biostat.umn.edu.
    Bioinformatics 10/2009; 25(24):3213-20. · 5.47 Impact Factor
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    ABSTRACT: Untreated HIV-1 infection progresses through acute and asymptomatic stages to AIDS. Although each of the three stages has well-known clinical, virologic, and immunologic characteristics, much less is known of the molecular mechanisms underlying each stage. In this study, we report lymphatic tissue microarray analyses, revealing for the first time stage-specific patterns of gene expression during HIV-1 infection. We show that although there is a common set of key genes with altered expression throughout all stages, each stage has a unique gene expression signature. The acute stage is most notably characterized by increased expression of hundreds of genes involved in immune activation, innate immune defenses (e.g., RIG-1, MDA-5, TLR7 and TLR8, PKR, APOBEC3B, 3F, 3G), adaptive immunity, and in the proapoptotic Fas-Fas ligand pathway. Yet, quite strikingly, the expression of nearly all acute stage genes return to baseline levels in the asymptomatic stage, accompanying partial control of infection. This transition from acute to asymptomatic stage is tied to increased expression of a diverse array of immunosuppressive genes (e.g., CLEC12B, ILT4, galectin-3, CD160, BCMA, FGL2, LAG3, GPNMB). In the AIDS stage, decreased expression of numerous genes involved in T cell signaling identifies genes contributing to T cell dysfunction. These common and stage-specific gene expression signatures identify potential molecular mechanisms underlying the host response and the slow, natural course of HIV-1 infection.
    The Journal of Immunology 09/2009; 183(3):1975-82. · 5.52 Impact Factor

Publication Stats

3k Citations
379.58 Total Impact Points

Institutions

  • 2003–2014
    • University of Minnesota Duluth
      • Medical School
      Duluth, Minnesota, United States
  • 2002–2009
    • University of Minnesota Twin Cities
      • • Division of Biostatistics
      • • Department of Medicine
      • • Department of Microbiology
      • • Division of Pediatric Infectious Diseases
      Minneapolis, MN, United States
  • 2008
    • Hennepin County Medical Center
      Minneapolis, Minnesota, United States