VM: Anatomy, Physiology and Cell Biology
Center for Comparative Medicine
Leader, Infectious Disease Unit
California National Primate Research Center
University of California, Davis
Research Interest: 1) Determining the role of monocyte/macrophages in the pathogenesis of infectious diseases, chronic inflammation and aging; 2) Examining the immunology of aging, and; 3) Assessing the roles of macrophages in the pathogenesis of TB using the macaque model of TB/SIV.
The long-term goal of our laboratory is to understand how changes in monocyte/macrophages contribute to disease pathogenesis and to use this information to develop preventive and/or therapeutic strategies against a variety of infectious diseases and the harmful effects of chronic inflammation. Below are examples of our ongoing research on different aspects of this research theme.
Role of monocyte/macrophages in infectious disease
We previously reported that the increased turnover rate of blood monocytes and tissue macrophages positively correlates with progression to terminal AIDS in SIV-infected adult rhesus macaques (Hasegawa, Liu et al. 2009, Burdo, Soulas et al. 2010). The timing of increased monocyte turnover is driven by a mechanism that is different from HIV-induced chronic immune activation and CD4+ T-cell depletion (Brenchley, Price et al. 2006, Okoye, Meier-Schellersheim et al. 2007). Instead, this appears to result from an effort by the immune system to replace the tissue macrophages damaged during HIV/SIV infection to re-establish homeostasis. The increase in monocyte turnover, which is due to high tissue demand for macrophages, thus predicts, and seems to dictate the tempo of progression to AIDS more consistently than does a low CD4+ T-cell count alone. Differentiation Kinetics of Blood Monocytes and Dendritic Cells in Macaques. Our data from in vivo BrdU experiments led us to characterize the kinetics and dynamics of myeloid cell subset development. Results from these studies provided valuable information about the turnover, kinetics, and maturation of the different subsets of monocytes and DC using approaches that cannot readily be performed in humans. These studies support further analyses to continue examining the unique myeloid cell origins that may be applied to address disease pathogenesis mechanisms, and to develop new intervention strategies for diseases in humans (Sugimoto, Hasegawa et al. 2015). A Critical Role for Monocyte/Macrophages in the Rapid Progression to AIDS in Pediatric SIV-Infected Rhesus Macaques. Infant humans and rhesus macaques infected with HIV or SIV, respectively, present with higher viral loads and progress more rapidly to AIDS than do adults. Activated memory CD4+ T cells in intestinal tissues are major primary target cells for SIV/HIV infection and massive depletion of these CD4+ T cells is considered a major cause of immunodeficiency. Monocytes and macrophages are also important components of innate immunity, and are clearly major targets of HIV/SIV infection. We originally reported that high peripheral blood monocyte turnover rate was predictive of progression to AIDS in adult SIV-infected macaques. Our more recent studies focused on determining whether infection of monocytes/macrophages contributes to the rapid progression to AIDS in SIV-infected newborn rhesus macaques. Uninfected infant rhesus macaques exhibited a relatively higher baseline monocyte turnover than adults. Soon after SIV infection in infant macaques, the monocyte turnover dramatically increased further and remained high during progression to AIDS. The higher baseline monocyte turnover in infant macaques and subsequent macrophage damage by SIV infection may help explain the basis of higher sustained viral loads and more rapid disease progression to AIDS after HIV infection in infants (Sugimoto, Merino et al. 2017, Merino et al. 2017). Preferential Destruction of Interstitial Macrophages over Alveolar Macrophages as a Cause of Pulmonary Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques. This study demonstrates for the first time that the AIDS virus differentially impacts two distinct subsets of lung macrophages. The predominant macrophages harvested by bronchoalveolar lavage (BAL), alveolar macrophages (AMs), are routinely used in studies on human lung macrophages. We have demonstrated in macaques that AMs are long-lived cells that and exhibit relatively low turnover. The interstitial macrophages (IMs), however, are not recovered with BAL and are shorter-lived exhibiting higher baseline turnover rates distinct from AMs (Cai, Sugimoto et al. 2014). We then examined the effects of SIV infection on AMs in BAL fluid and IMs in lung tissue of rhesus macaques. Severity of SIV infection correlated with increased monocyte turnover and greater degree of massive cell death of IMs that contributed to lung tissue damage. Conversely, SIV infection induced minimal cell death of AMs, and these cells maintained a lower turnover rate throughout the duration of infection. This indicates that SIV produces lung tissue damage through destruction of IMs, whereas the longer-lived AMs may serve as a virus reservoir to facilitate HIV persistence (Cai, Sugimoto et al. 2015a, Cai, Sugimoto et al. 2015b). Macrophage damage by SIV promotes TB reactivation in the TB/SIV rhesus co-infection model. CD4+ T cell depletion by HIV infection is considered a major cause of tuberculosis (TB) reactivation. We recently reported, however, that in rhesus macaques co-infected with SIV and Mtb, massive SIV infection and apoptosis of lung macrophages better correlated with the transition from latent TB infection (LTBI) to TB reactivation. Interestingly, all of the SIV and Mtb co-infected monkeys exhibited declining numbers of CD4+ T cells in the lung regardless of whether they expressed reactivation of TB or maintained LTBI. Thus, damage to monocytes/macrophages by SIV infection appeared more impactful on Mtb reactivation during Mtb/SIV co-infection and more predictive of disease progression than declining numbers of CD4+ T cells (Kuroda et al. 2018).
Immunology of Aging
Our studies have defined groups of NHPs that exhibit putative healthy vs. less healthy aging profiles (Didier, Sugimoto et al. 2012). Our ongoing studies examine changes in macrophages related to inflammation, apoptosis, and reservoir effects that impact increased susceptibility to infectious diseases during aging using the rhesus macaque model.