Background Human cytomegalovirus (CMV) infection is associated with inferior survival in renal transplant patients, and ganciclovir (GCV) prophylaxis is associated with improved survival. In a murine CMV (MCMV) renal transplantation model, ganciclovir prophylaxis improved innate infiltrates and allograft damage during the period of prophylaxis. In this study, late effects were examined after the discontinuation of prophylaxis. Methods MCMV D+/R- and D-/R- allogeneic transplants were performed with cyclosporine immunosuppression. One D+/R- cohort received ganciclovir prophylaxis for 14 days after transplantation followed by 28 days without ganciclovir. At 42 days after transplantation, grafts were analyzed for histologic tissue damage and immune infiltrates. Another D+/R- cohort was treated with anti-NK1.1 antibodies for 14 days after transplantation and compared with animals without natural killer (NK) cell depletion. Results At day 42, MCMV-infected transplants had higher damage scores (15.6±0.6) compared with uninfected transplants (8.3±0.9; P<0.01), which improved in ganciclovir-treated allografts (9.5±1.4). MCMV-infected grafts contained greater frequencies of NK cell and myeloid infiltrates compared with uninfected grafts (P<0.05), which decreased in the ganciclovir-treated grafts. NK cell depletion improved allograft histology of MCMV-infected grafts. Conclusions MCMV infection exacerbates late renal allograft damage and is associated with NK and myeloid cell infiltrates. Ganciclovir prophylaxis reduces allograft injury and NK cell and myeloid infiltrates even after the cessation of prophylaxis. NK cell depletion in MCMV-infected transplants also improves histology. These results suggest that ganciclovir prophylaxis may have a long-term beneficial effect on CMV-infected renal allografts and suggest a potential role for NK cells in the pathogenesis of CMV-associated allograft injury.
insomnia and energy-mania in negative terms (4/6 and 3/6 respectively); others found them positive (2/6 and 3/6 respectively).7 described steroids as the most difficult part of having GT; 2 reported no adverse effects.Positively, 4 reported improved joint pain while taking steroids.Conclusion(s): Over half of PwH described steroids as the worst part of GT, impacting themselves and their families due to adverse side effects.Ensuring these impacts are understood, identified quickly, and dealt with appropriately and effectively is essential if PwH are to obtain the maximum benefit from GT.There remains a need for studies of less toxic approaches to immunosuppression.
Alabama at Birmingham, Genetics, Birmingham, United States Background: Human cytomegalovirus (CMV) infection is associated with adverse outcomes in renal transplantation, but the pathogenesis remains cryptic. Ganciclovir prophylaxis is associated with improved survival in some but not all clinical studies. In a murine CMV (MCMV) donor positive/recipient negative allogeneic renal transplant model, MCMV exacerbated innate infiltrates and early histologic injury at 2 weeks post-transplant, and these parameters improved with ganciclovir prophylaxis. The effect of ganciclovir prophylaxis on late allograft histology has not been examined. Methods: Murine CMV (MCMV) infected Balb/c donor kidneys were transplanted orthotopically into C57Bl/6 recipients with cyclosporine immunosuppression (CMV group). Control transplants were performed using uninfected Balb/c donors (control group). Ganciclovir (GCV) prophylaxis was administered for 14 days post-transplant to one cohort of MCMV infected transplants (GCV group). Animals were sacrificed at day 42 post-transplant. Histology was scored according to an established grading scale (grade 0-3 for 9 criteria, maximum score 27) by a veterinary pathologist blinded to sample identity. Immune infiltrates were examined by flow cytometry in allograft kidneys, livers, and spleens. Results: At day 42, CMV transplants had higher aggregate damage scores (average 14.5) compared to control uninfected transplants (average 10.25). Allografts with GCV prophylaxis had lower damage scores (average 9.5) and appeared histologically more similar to uninfected grafts than to CMV infected grafts. Analysis of leukocyte infiltrates by flow cytometry revealed greater frequencies of CD45+ cells in CMV infected compared to uninfected grafts. Of the CD45+ population, CMV infected and uninfected grafts had similar frequencies of CD4+, CD8+, and CD19+ lymphocytes, but CMV infected grafts contained higher frequencies of CD49b+ and Gr-1+ cells compared to uninfected grafts. GCV prophylaxis reduced the frequency of Gr-1+ infiltrates but not CD49b+ infiltrates, and also contained a lower frequency of CD11b+/CD204+ cells. Grafts with GCV prophylaxis contained greater frequencies of CD4+ cells compared to both CMV and control grafts. Analysis of infiltrates in livers and spleens from allograft recipients showed no differences in frequencies of any of these leukocyte subsets between control, CMV, and GCV treated recipients. Conclusion: CMV infection exacerbates late renal allograft damage by histologic criteria and is associated with ongoing infiltration of innate leukocyte subsets including NK cells and myeloid cells. Allografts with GCV prophylaxis had less severe allograft injury and appeared histologically similar to uninfected grafts, even though prophylaxis had been discontinued for 28 days prior to terminal sacrifice. GCV prophylaxis was associated with reduction of myeloid and macrophage infiltrates but not NK infiltrates, and additionally was associated with increased CD4+ infiltrates. These results suggest that ganciclovir prophylaxis may modulate long-term CMV effects upon allograft injury, which may possibly be related to differences in recruitment of innate and CD4+ leukocytes even after cessation of prophylaxis. Intragraft responses differed from leukocyte populations in the liver and spleen, suggesting that systemic responses may not necessarily serve as surrogates for the intragraft inflammatory response.
ABSTRACT Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-α)-neutralizing antibodies decreased the frequency of CD45 + Ly6C hi CD11b + CCR2 + activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMV-infected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-α is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain. IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a mouse model that recapitulates characteristics of the brain infection described in human infants, we have shown that TNF-α plays a key role in brain inflammation, including recruitment of inflammatory mononuclear cells. Neutralization of TNF-α normalized neurodevelopmental abnormalities in infected mice, providing evidence that virus-induced inflammation is a major component of disease in the developing brain. These results suggest that interventions limiting inflammation associated with the infection could potentially improve the neurologic outcome of infants infected in utero with HCMV.
Although human cytomegalovirus (HCMV) is a known cause of sensorineural hearing loss in infants with congenital HCMV (cCMV) infections, mechanisms that contribute to sensorineural hearing loss (SNHL) in infants with cCMV infection are not well defined. Using a murine model of CMV infection during auditory development, we have shown that peripheral infection of newborn mice with murine CMV (MCMV) results in focal infection of the cochlea and virus-induced cochlear inflammation. Approximately 50%-60% of infected mice exhibited increased auditory brainstem response (ABR) thresholds across a range of sound frequencies. Histological analyses of the cochlea in MCMV-infected mice with elevated ABR thresholds revealed preservation of hair cell (HC) number and morphology in the organ of Corti. In contrast, the number of spiral ganglion neurons (SGN), synapses, and neurites connecting the cochlear HC and SGN nerve terminals were decreased. Decreasing cochlear inflammation by corticosteroid treatment of MCMV-infected mice resulted in preservation of SGN and improved auditory function. These findings show that virus-induced cochlear inflammation during early auditory development, rather than direct virus-mediated damage, could contribute to histopathology in the cochlea and altered auditory function without significant loss of HCs in the sensory epithelium.
In children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, virological characteristics and correlation with disease severity have not been extensively studied. The primary objective in this study is to determine the correlation between SARS-CoV-2 viral load (VL) in infected children with age, disease severity, and underlying comorbidities.
Testing of paired midturbinate (MT) nasal and nasopharyngeal (NP) swabs, collected by trained personnel from 40 patients with coronavirus disease 2019 (COVID-19), showed that more NP (76/95 [80%]) than MT swabs tested positive (61/95 [64%]) (P = .02). Among samples collected a week after study enrollment, fewer MT than NP samples were positive (45% vs 76%; P = .001).
