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Open Access Publications from the University of California

Scholarly Works (40 results)

  • Thesis
  • Peer Reviewed
UC Davis Electronic Theses and Dissertations (2022)

Host immune responses and the host immune system itself are shaped by interactions with environmental factors including diet, commensal microbiota, and pathogens. The microbiome, defined as a community of microorganisms and their interactions with their surrounding environmental conditions, further interacts with structural elements, metabolites, and signaling molecules from other microorganisms and the host. These networks of interactions result in heterogeneous immune responses and affect our ability to develop immunotherapies or vaccines that are universally applicable to the entire population. Untangling these interactions between environmental factors and the host immune system in the presence of many covariates has been difficult but has been increasingly aided by advances in technologies and our ability to process multi-dimensional data sets. Understanding the extent of environmental influence on the host immune system is important to further identify the important factors to drive desired immune responses, especially for developing cancer therapies and vaccines. In this dissertation, we used metagenomics, transcriptomics, and single-cell immunophenotyping methods to understand important influences on the immune system, including diet, microbiome, latent viral infections, and viral vector-based vaccination. We found that dietary intervention can lead to transient changes in the gut microbiome without causing dramatic changes to the infant immune system, suggesting limited effects of host-microbe interactions over a short time period. Latent viral infections have much greater impacts on the host immune system and can additionally subvert or supplant relationships between the host and other microbes. Latent viral infections also resulted in different vaccine responses that can be observed at the transcriptomic level. Overall, we identified latent infection with cytomegalovirus (CMV) as one of the major contributors to different immune responses in different individuals, using rhesus macaque as an animal model. Future work targeting pathways changed by CMV may be important for understanding heterogeneous immune responses and for further development of CMV-based vaccine vectors.

    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2022)
    Nonhuman primates are critically important animal models in which to study complex human diseases, understand biological functions, and address the safety of new diagnostics and therapies proposed for human use. They have genetic, physiologic, immunologic, and developmental similarities when compared to humans and therefore provide important preclinical models of human health and disease. This review highlights select research areas that demonstrate the importance of nonhuman primates in translational research. These include pregnancy and developmental disorders, infectious diseases, gene therapy, somatic cell genome editing, and applications of in vivo imaging. The power of the immune system and our increasing understanding of the role it plays in acute and chronic illnesses are being leveraged to produce new treatments for a range of medical conditions. Given the importance of the human immune system in health and disease, detailed study of the immune system of nonhuman primates is essential to advance preclinical translational research. The need for nonhuman primates continues to remain a high priority, which has been acutely evident during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) global pandemic. Nonhuman primates will continue to address key questions and provide predictive models to identify the safety and efficiency of new diagnostics and therapies for human use across the lifespan.
      Cover page: Nonhuman Primates in Translational Research
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2022)
      Nonhuman primates are essential for the study of human disease and to explore the safety of new diagnostics and therapies proposed for human use. They share similar genetic, physiologic, immunologic, reproductive, and developmental features with humans and thus have proven crucial for the study of embryonic/fetal development, organ system ontogeny, and the role of the maternal-placental-fetal interface in health and disease. The fetus may be exposed to a variety of inflammatory stimuli including infectious microbes as well as maternal inflammation, which can result from infections, obesity, or environmental exposures. Growing evidence supports that inflammation is a mediator of fetal programming and that the maternal immune system is tightly integrated with fetal-placental immune responses that may set a postnatal path for future health or disease. This review addresses some of the unique features of the nonhuman primate model system, specifically the rhesus monkey (Macaca mulatta), and importance of the species for studies focused on organ system ontogeny and the impact of viral teratogens in relation to development and congenital disorders.
        Cover page: Translational Utility of the Nonhuman Primate Model
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2007)
        The impact of regulatory T cells (T reg cells) on the course of HIV and SIV disease is unknown. T reg cells could suppress protective antiviral responses and accelerate disease progression. Alternatively, these cells might block T cell activation and thereby limit viral replication as well as activation-associated immunopathology. Given the higher frequency of T reg cells known to be present during human fetal ontogeny, such influences may be most important in the context of perinatal infection. We found that infant macaques had higher fractions of CD4(+)CD25(+)CD127(low)FoxP3(+) T reg cells in the peripheral blood and in lymphoid tissues, and that these T reg cells showed greater in vitro suppressive activity on a per cell basis. Infant and adult macaques were infected with SIVmac251 to test the influence of the T reg cell compartment on SIV-specific immune responses. After infection with SIV, most (three out of four) infant macaques had persistently high viral loads, weak and transient SIV-specific CD4(+) and CD8(+) T cell responses, and rapid disease progression. T reg cells in the infant but not in the adult directly suppressed SIV-specific CD4(+) T cell responses, which were detectable only after depletion of T reg cells. In the case of both the infant and the adult macaque, T reg cells were not able to directly suppress SIV-specific CD8(+) T cell responses and had no apparent effect on T cell activation. In aggregate, these observations suggest that the T reg cell compartment of the infant macaque facilitates rapid disease progression, at least in part by incapacitating SIV-specific CD4(+) T cell responses.
          Cover page: Suppression of SIV-specific CD4+ T cells by infant but not adult macaque regulatory T cells: implications for SIV disease progression
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2012)
          The mechanisms by which some HIV-infected subjects resist disease progression, whereas others progress rapidly, are incompletely understood. Viral and host genetic factors, such as nef deletions and major histocompatibility complex alleles, explain a portion of the observed variability. However, it has been difficult to identify host immune functions that may be present before infection and that allow resistance to lentiviral disease progression. Here, we show that simian immunodeficiency virus replication in the infected rhesus macaque is limited by the size of the preexisting T helper 17 (T(H)17) cell compartment: Animals with a high representation of such cells in blood and intestinal tissue before infection experienced peak and set-point viral loads about one log unit lower than those with a lower representation of T(H)17 cells. Reciprocally, treatment of macaques with interleukin-2 and granulocyte colony-stimulating factor before infection led to depletion of T(H)17 cells, reduction of the ratio between T(H)17 cells and CD3(+)CD4(+)CD25(+)CD127(low) regulatory T cells, and higher viral loads for 6 months after infection. These results demonstrate that the composition of the host immune system before infection has an influence on the course of disease after infection. Furthermore, to the extent that this influence shapes and interacts with T cell-mediated responses to virus, our findings provide a new framework for understanding interindividual variation in responses to therapies and vaccines against HIV.
            Cover page: SIV Replication in the Infected Rhesus Macaque Is Limited by the Size of the Preexisting TH17 Cell Compartment
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2022)
            Idiopathic chronic diarrhea (ICD) is a little understood common clinical problem in captive rhesus macaques claiming 33% of medical culls unrelated to research. The eukaryotic virome in digestive tract tissues collected at necropsy from nine animals with ICD was characterized using viral metagenomics. We compared the distribution of viral reads in tissues and mucosal scrapings from the stomach, duodenum, jejunum, ileum, and the proximal, transverse, and distal colons. In situ hybridization (ISH) using viral probes were performed on fixed tissues. Deep sequencing revealed multiple viruses in the Parvoviridae and Picornaviridae family. Tissues and mucosal scraping from the same locations showed closely related viral reads contents while different gut tissues from the same animal varied widely. ISH showed punctuated staining for both RNA and DNA viruses in the distal colon. Parvovirus staining was also detected in the stomach/duodenum/jejunum in distinct oval-shaped structures. The location of enteric viral nucleic acid differed widely between different viral families and along the length of the digestive tract.
              Cover page: Enteric Viruses Nucleic Acids Distribution along the Digestive Tract of Rhesus Macaques with Idiopathic Chronic Diarrhea
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2011)

              Background

              the immune reconstitution inflammatory syndromes (IRIS) are a spectrum of inflammatory conditions associated with opportunistic infections and occurring in approximately16% of human immunodeficiency type 1 (HIV-1)-infected patients given antiretroviral therapy. It has been proposed that these conditions are linked by a dysregulated immune system that is prone to exaggerated responses. However, immunologic studies have been limited by the availability of longitudinal samples from patients with IRIS and appropriate matched control subjects. Cytomegalovirus (CMV) immune recovery uveitis (IRU) is an IRIS occurring in up to 38% of patients with CMV retinitis. Although the pathologic immune responses occur in the eye, immune dysregulation that allows for development of pathologic responses is presumably caused by faulty systemic immune cell reconstitution.

              Methods

              we examined CMV-specific T cell responses, regulatory T (T(reg)) cell function and polyclonal T cell responses, including IL-17 production, in 25 patients with CMV IRU and 49 immunorestored control subjects with CMV retinitis who did not develop IRU.

              Results

              patients with CMV IRU had poor CMV-specific CD4(+) T cell responses, as compared with control subjects, whereas CD8(+) T cell responses were comparable. Patients with CMV IRU were characterized by smaller numbers of circulating Th17 cells. Deficiency in anti-CMV responses was not associated with differences in T(reg) cell function.

              Conclusions

              the T(reg) cell compartment is intact in patients with CMV IRU, and these patients do not develop exaggerated systemic CMV-specific or polyclonal immune responses. Cases are instead characterized by more profound depletion of Th17 cells and poor antiviral immune responses. CMV IRU may be most likely to develop in persons experiencing the greatest degree of immune dysfunction before initiating highly active antiretroviral therapy.
                Cover page: Development of Cytomegalovirus (CMV) Immune Recovery Uveitis Is Associated with Th17 Cell Depletion and Poor Systemic CMV-Specific T Cell Responses
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2021)
                While recent changes in treatment have reduced the lethality of idiopathic chronic diarrhea (ICD), this condition remains one of the most common causes of rhesus macaque deaths in non-human primate research centers. We compared the viromes in fecal swabs from 52 animals with late stage ICD and 41 healthy animals. Viral metagenomics targeting virus-like particles was used to identify viruses fecally shed by each animal. Five viruses belonging to the Picornaviridae, one to the Caliciviridae, one to the Parvoviridae, and one to the Adenoviridae families were identified. The fraction of reads matching each viral species was then used to estimate and compare viral loads in ICD cases versus healthy controls. None of the viruses detected in fecal swabs were strongly associated with ICD.
                  Cover page: Idiopathic Chronic Diarrhea in Rhesus Macaques Is Not Associated with Enteric Viral Infections
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2021)
                  Zika virus is a teratogen similar to other neurotropic viruses, notably cytomegalovirus and rubella. The goal of these studies was to address the direct impact of Zika virus on fetal development by inoculating early gestation fetal rhesus monkeys using an ultrasound-guided approach (intraperitoneal vs. intraventricular). Growth and development were monitored across gestation, maternal samples collected, and fetal tissues obtained in the second trimester or near term. Although normal growth and anatomical development were observed, significant morphologic changes were noted in the cerebral cortex at 3-weeks post-Zika virus inoculation including massive alterations in the distribution, density, number, and morphology of microglial cells in proliferative regions of the fetal cerebral cortex; an altered distribution of Tbr2+ neural precursor cells; increased diameter and volume of blood vessels in the cortical proliferative zones; and a thinner cortical plate. At 3-months postinoculation, alterations in morphology, distribution, and density of microglial cells were also observed with an increase in blood vessel volume; and a thinner cortical plate. Only transient maternal viremia was observed but sustained maternal immune activation was detected. Overall, these studies suggest persistent changes in cortical structure result from early gestation Zika virus exposure with durable effects on microglial cells.
                    Cover page: Fetal Rhesus Monkey First Trimester Zika Virus Infection Impacts Cortical Development in the Second and Third Trimesters
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2015)
                    Early infant diet has significant impacts on the gut microbiota and developing immune system. We previously showed that breast-fed and formula-fed rhesus macaques develop significantly different gut microbial communities, which in turn are associated with different immune systems in infancy. Breast-fed animals manifested greater T cell activation and proliferation and harbored robust pools of T helper 17 (TH17) cells. These differences were sustained throughout the first year of life. Here we examine groups of juvenile macaques (approximately 3 to 5 y old), which were breast-fed or formula-fed in infancy. We demonstrate that juveniles breast-fed in infancy maintain immunologic differences into the fifth year of life, principally in CD8(+) memory T cell activation. Additionally, long-term correlation networks show that breast-fed animals maintain persistent relationships between immune subsets that are not seen in formula-fed animals. These findings demonstrate that infant feeding practices have continued influence on immunity for up to 3 to 5 y after birth and also reveal mechanisms for microbial modulation of the immune system.
                      Cover page: Persistent effects of early infant diet and associated microbiota on the juvenile immune system
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