Efectos indirectos de la infección por citomegalovirus en una cohorte de receptores de trasplante renal

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 09-05-2022El citomegalovirus (CMV) es un miembro de la familia Herpesviridae. Tras la primoinfección, el CMV permanece latente en las células del huésped pudiendo reactivarse en ciertas situaciones de inmunosupresión como ocurre tras el trasplante de órgano sólido (TOS). En estos pacientes, el CMV produce un daño tisular directo que puede manifestarse en forma de enfermedad clínica sintomática. Además, la infección por CMV en receptores de TOS se ha asociado con la aparición de una serie de fenómenos de modulación inmune comúnmente denominados “efectos indirectos” que resultan de la interacción del virus con el sistema inmune del huésped y de la inflamación tisular asociada. En el receptor de trasplante renal (TR) se ha descrito, en relación con la exposición previa a la infección por CMV, un incremento de la incidencia de infecciones causadas por otros microorganismos, de viremia y nefropatía asociada al poliomavirus BK, y de eventos atero-trombóticos...Cytomegalovirus (CMV) is a member of the Herpesviridae family. After primoinfection, CMV can remain in host cells and reactivate in certain situations of immunosuppression, with solid organ transplantation (SOT) as one of the most common scenarios. In these patients, CMV may cause a direct tissue injury in the form of symptomatic clinical disease. However, CMV infection in SOT recipients has been also associated with the development of immunomodulatory phenomena (the so-called "indirect effects") that result from the interaction of the virus with the host's immune system and the associated tissue inflammation. In kidney transplant (KT) recipients previously exposed to CMV there has been described an increased risk of post-transplant non-CMV infection, BK polyomavirus infection and associated nephropathy, and post-transplant atherosclerotic (PAE) and thrombotic (PTE) events...Fac. de MedicinaTRUEunpu

Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients

Erratum for Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients. Tajuelo A, Carretero O, García-Ríos E, López-Siles M, Cano O, Vázquez M, Más V, Rodríguez-Goncer I, Lalueza A, López-Medrano F, Juan RS, Fernández-Ruiz M, Aguado JM, McConnell MJ, Pérez-Romero P. Front Immunol. 2022 Apr 25;13:878812. doi: 10.3389/fimmu.2022.878812. eCollection 2022. PMID: 35547738 Free PMC article.Introduction: There is robust evidence indicating that the SARS-CoV-2-specific humoral response is associated with protection against severe disease. However, relatively little data exist regarding how the humoral immune response at the time of hospital admission correlates with disease severity in unimmunized patients. Our goal was toidentify variables of the humoral response that could potentially serve as prognostic markers for COVID-19 progressionin unvaccinated SARS-CoV-2 patients. Methods: A prospective cross-sectional study was carried out in a cohort of 160 unimmunized, adult COVID-19 patients from the Hospital Universitario 12Octubre. Participants were classified into four clinical groups based on disease severity: non-survivors with respiratory failure (RF), RF survivors, patients requiring oxygen therapy and those not receiving oxygen therapy. Serum samples were taken on admission and IgM, IgG, IgG subclass antibody titers were determined by ELISA, and neutralizing antibody titersusing a surrogate neutralization assay. The differences in the antibody titers between groups and the association between the clinical and analytical characteristics of the patients and the antibody titers were analyzed. Results: Patients that developed RF and survived had IgM titers that were 2-fold higher than non-survivors (p = 0.001), higher levels of total IgG than those who developed RF and succumbed to infection (p< 0.001), and than patients who required oxygen therapy (p< 0.05), and had 5-fold higher IgG1 titers than RF non-survivors (p< 0.001) and those who needed oxygen therapy (p< 0.001), and 2-fold higher than patients that did not require oxygen therapy during admission (p< 0.05). In contrast, RF non-survivorshad the lowest neutralizing antibodylevels, which were significantly lower compared those with RF that survived (p = 0.03). A positive correlation was found between IgM, total IgG, IgG1 and IgG3 titers and neutralizing antibody titers in the total cohort (p ≤ 0.0036). Conclusions: We demonstrate that patients with RF that survived infection had significantly higher IgM, IgG, IgG1 and neutralizing titers compared to patients with RF that succumb to infection, suggesting that using humoral response variables could be used as a prognostic marker for guiding the clinical management of unimmunized patients admitted to the hospital for SARS-CoV-2 infection.This work was supported by Mutua Madrileña Foundation (2020/0056) “Plan Nacional de I+D+I” and Instituto de Salud Carlos III (COVID-19 Research Call COV20/00181 and COV20_00679), Subdirección General de Redes y Centros de Investigación Cooperativa, Spanish Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016) - co-financed by the European Development Regional Fund (EDRF) and the European Social Fund (ESF) "A way to achieve Europe- The ESF invests in your future". Red de Enfermedades Infecciosas (CIBERINFEC), CB21/13/00079. EG-R is supported by the Sara Borrell Program (CD18CIII/00007), MLS is supported by the Sara Borrell Program (CD17CIIII/00017), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades., and AT is supported by the Garantía Juvenil Program of the Comunidad Autonoma de Madrid. IRG holds a research training contract “Río Hortega” (CM19/00163) and MFR a research contract “Miguel Servet” (CP18/00073), both from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation.S

Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients

Risk stratification for cytomegalovirus (CMV) infection after kidney transplantation (KT) remains to be determined. Since endosomal toll-like receptors (TLRs) are involved in viral sensing, we investigated the impact of common single-nucleotide polymorphisms (SNPs) located within TLR3 and TLR9 genes on the occurrence of overall and high-level (≥1,000 IU/ml) CMV infection in a cohort of 197 KT recipients. Homozygous carriers of the minor allele of TLR3 (rs3775291) had higher infection-free survival compared with reference allele carriers (60.0% for TT versus 42.3% for CC/CT genotypes; P-value = 0.050). Decreased infection-free survival was observed with the minor allele of TLR9 (rs352139) (38.2% for TC/CC versus 59.3% for TT genotypes; P-value = 0.004). After multivariable adjustment, the recessive protective effect of the TLR3 (rs3775291) TT genotype was confirmed (adjusted hazard ratio [aHR]: 0.327; 95% CI: 0.167–0.642; P-value = 0.001), as was the dominant risk-conferring effect of TLR9 (rs352139) TC/CC genotypes (aHR: 1.865; 95% CI: 1.170–2.972; P-value = 0.009). Carriers of the TLR9 (rs352139) TC/CC genotypes showed lower CMV-specific interferon-γ-producing CD4+ T-cell counts measured by intracellular cytokine staining compared with the TT genotype (median of 0.2 versus 0.7 cells/μl; P-value = 0.003). In conclusion, TLR3/TLR9 genotyping may inform CMV infection risk after KT

DataSheet1_Impact of polymorphisms in genes orchestrating innate immune responses on replication kinetics of Torque teno virus after kidney transplantation.PDF

Background: Torque teno virus (TTV) DNAemia has been proposed as a surrogate marker of immunosuppression after kidney transplantation (KT), under the assumption that the control of viral replication is mainly exerted by T-cell-mediated immunity. However, Tthe impact on post-transplant TTV kinetics of single genetic polymorphisms (SNPs) in genes orchestrating innate responses remains unknown. We aimed to characterize the potential association between 14 of these SNPs and TTV DNA levels in a single-center cohort of KT recipients.Methods: Plasma TTV DNAemia was quantified by real-time PCR in 221 KT recipients before transplantation (baseline) and regularly through the first 12 post-transplant months. We performed genotyping of the following SNPs: CTLA4 (rs5742909, rs231775), TLR3 (rs3775291), TLR9 (rs5743836, rs352139), CD209 (rs735240, rs4804803), IFNL3 (rs12979860, rs8099917), TNF (rs1800629), IL10 (rs1878672, rs1800872), IL12B (rs3212227) and IL17A (rs2275913).Results: The presence of the minor G allele of CD209 (rs4804803) in the homozygous state was associated with undetectable TTV DNAemia at the pre-transplant assessment (adjusted odds ratio: 36.96; 95% confidence interval: 4.72–289.67; p-value = 0.001). After applying correction for multiple comparisons, no significant differences across SNP genotypes were observed for any of the variables of post-transplant TTV DNAemia analyzed (mean and peak values, areas under the curve during discrete periods, or absolute increments from baseline to day 15 and months 1, 3, 6 and 12 after transplantation).Conclusion: The minor G allele of CD209 (rs4804803) seems to exert a recessive protective effect against TTV infection in non-immunocompromised patients. However, no associations were observed between the SNPs analyzed and post-transplant kinetics of TTV DNAemia. These negative results would suggest that post-transplant TTV replication is mainly influenced by immunosuppressive therapy rather than by underlying genetic predisposition, reinforcing its clinical application as a biomarker of adaptive immunity.</p