Colombian consensus recommendations for diagnosis, management and treatment of the infection by SARS-COV-2/ COVID-19 in health care facilities - Recommendations from expert´s group based and informed on evidence

La Asociación Colombiana de Infectología (ACIN) y el Instituto de Evaluación de Nuevas Tecnologías de la Salud (IETS) conformó un grupo de trabajo para desarrollar recomendaciones informadas y basadas en evidencia, por consenso de expertos para la atención, diagnóstico y manejo de casos de Covid 19. Estas guías son dirigidas al personal de salud y buscar dar recomendaciones en los ámbitos de la atención en salud de los casos de Covid-19, en el contexto nacional de Colombia

Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?

Natural killer (NK) cells express inhibiting receptors (iNKRs), which specifically bind MHC-I molecules on the surface of healthy cells. When the expression of MHC-I on the cell surface decreases, which might occur during certain viral infections and cancer, iNKRs lose inhibiting signals and the infected cells become target for NK cell activation (missing-self detection). Although the detection of MHC-I deficient cells can be achieved by conserved receptor-ligand interactions, several iNKRs are encoded by gene families with a remarkable genetic diversity, containing many haplotypes varying in gene content and allelic polymorphism. So far, the biological function of this expansion within the NKR cluster has remained poorly understood. Here, we investigate whether the evolution of diverse iNKRs genes can be driven by a specific viral immunoevasive mechanism: selective MHC downregulation. Several viruses, including EBV, CMV, and HIV, decrease the expression of MHC-I to escape from T cell responses. This downregulation does not always affect all MHC loci in the same way, as viruses target particular MHC molecules. To study the selection pressure of selective MHC downregulation on iNKRs, we have developed an agent-based model simulating an evolutionary scenario of hosts infected with herpes-like viruses, which are able to selectively downregulate the expression of MHC-I molecules on the cell surface. We show that iNKRs evolve specificity and, depending on the similarity of MHC alleles within each locus and the differences between the loci, they can specialize to a particular MHC-I locus. The easier it is to classify an MHC allele to its locus, the lower the required diversity of the NKRs. Thus, the diversification of the iNKR cluster depends on the locus specific MHC structure

A Coevolutionary Arms Race between Hosts and Viruses Drives Polymorphism and Polygenicity of NK Cell Receptors

Natural killer cell receptors (NKRs) monitor the expression of major histocompatibility class I (MHC-I) and stress molecules to detect unhealthy tissue, such as infected or tumor cells. The NKR gene family shows a remarkable genetic diversity, containing several genes encoding receptors with activating and inhibiting signaling, and varying in gene content and allelic polymorphism. The expansion of the NKR genes is species-specific, with different species evolving alternative expanded NKR genes, which encode structurally different proteins, yet perform comparable functions. So far, the biological function of this expansion within the NKR cluster has remained poorly understood. To study the evolution of NKRs, we have developed an agent-based model implementing a coevolutionary scenario between hosts and herpes-like viruses that are able to evade the immune response by downregulating the expression of MHC-I on the cell surface. We show that hosts evolve specific inhibitory NKRs, specialized to particular MHC-I alleles in the population. Viruses in our simulations readily evolve proteins mimicking the MHC molecules of their host, even in the absence of MHC-I downregulation. As a result, the NKR locus becomes polygenic and polymorphic, encoding both specific inhibiting and activating receptors to optimally protect the hosts from coevolving viruses

Quantifying the Protection of Activating and Inhibiting NK Cell Receptors during Infection with a CMV-Like Virus

The responsiveness of natural killer (NK) cells is controlled by balancing signals from activating and inhibitory receptors. The most important ligands of inhibitory NK cell receptors are the highly polymorphic major histocompatibility complex (MHC) class I molecules, which allow NK cells to screen the cellular health of target cells. Although these inhibitory receptor-ligand interactions have been well characterized, the ligands for most activating receptors are still unknown. The mouse cytomegalovirus (MCMV) represents a helpful model to study NK cell-driven immune responses. Many studies have demonstrated that CMV infection can be controlled by NK cells via their activating receptors, but the exact contribution of the different signaling potential (i.e., activating vs. inhibiting) remains puzzling. In this study, we have developed a probabilistic model, which predicts the optimal specificity of inhibitory and activating NK cell receptors needed to offer the best protection against a CMV-like virus. We confirm our analytical predictions with an agent-based model of an evolving host population. Our analysis quantifies the degree of protection of each receptor type, revealing that mixed haplotypes (i.e., haplotypes composed of activating and inhibiting receptors) are most protective against CMV-like viruses, and that the protective effect depends on the number of MHC loci per individual. © 2014 Carrillo-Bustamante, Kesmir and de Boer

Virus Encoded MHC-Like Decoys Diversify the Inhibitory KIR Repertoire

<div><p>Natural killer (NK) cells are circulating lymphocytes that play an important role in the control of viral infections and tumors. Their functions are regulated by several activating and inhibitory receptors. A subset of these receptors in human NK cells are the killer immunoglobulin-like receptors (KIRs), which interact with the highly polymorphic MHC class I molecules. One important function of NK cells is to detect cells that have down-regulated MHC expression (missing-self). Because MHC molecules have non polymorphic regions, their expression could have been monitored with a limited set of monomorphic receptors. Surprisingly, the KIR family has a remarkable genetic diversity, the function of which remains poorly understood. The mouse cytomegalovirus (MCMV) is able to evade NK cell responses by coding “decoy” molecules that mimic MHC class I. This interaction was suggested to have driven the evolution of novel NK cell receptors. Inspired by the MCMV system, we develop an agent-based model of a host population infected with viruses that are able to evolve MHC down-regulation and decoy molecules. Our simulations show that specific recognition of MHC class I molecules by inhibitory KIRs provides excellent protection against viruses evolving decoys, and that the diversity of inhibitory KIRs will subsequently evolve as a result of the required discrimination between host MHC molecules and decoy molecules.</p></div

Viruses that down regulate MHC expression select for degenerate KIR molecules while viruses expressing decoy molecules drive the selection of specific receptors.

<p>(A)–(B) Single representative simulations in a population infected with highly specific KIRs (i.e. bits). (A) The number of MHC molecules recognized per receptor in a population infected with an MHC down-regulating virus. The initial KIR molecules happen to recognize different numbers of MHC molecules, as indicated by the numbers in the boxes. 40% of the KIR molecules recognized one MHC molecule (black line), and 60% recognized two MHC molecules (red line). Upon infection, new KIR receptors that happened to be more cross-reactive, i.e., recognizing three MHC molecules (green line) evolved, while the most specific KIRs decreased in frequency. (B) The specificity of the KIRs in a population infected with decoy viruses. 60% of the inital KIR molecules recognized one MHC molecule (black line), 20% recognized two MHC molecules (red line), and 20% happened to recognize three different MHC molecules (green line). Over time, the frequency of those KIR molecules recognizing only one MHC molecule increased and they take over the population. (C)–(D) The average number of MHC molecules recognized per KIR molecule. In populations with highly specific KIRs ( bits), this number decreases if the individuals are infected with a virus down-regulating MHC expression (C), whereas it increases in populations infected with decoy viruses (D). (E)–(F): The average number of MHC molecules recognized per haplotype. We observed a similar behaviour as in (C)–(D). The heavy lines represent the mean number of recognized MHC molecules over ten simulations. The different colors represent the specificity values ranging from to bits. The standard deviation is depicted by the dashed lines.</p

Schematic model description.

<p>(A) KIRs and MHC molecules are implemented as bitstrings. The receptor-ligand recognition is modeled via complementary matching. Here, the longest adjacent match is 6 bits long, and when the length of this match exceeds the threshold , the MHC molecules can be recognized by the KIR. (B) Description of the viral evasion mechanisms. The wild type virus can evolve MHC-downregulation and a decoy ligand for KIRs. The immune escape of the virus after evolution of the immunoevasive mechanisms is modeled by decreasing the clearance probability . The arrow-headed lines indicate the activation of the T cell or the NK cell, whereas the bar-headed lines indicate their inhibition.</p