SARS-CoV-2 Infection in Kidney Transplant Recipients: A Single-Centre Study of 20 Cases from India.

INTRODUCTION: The second wave of COVID-19 has spread across India causing unprecedented misery to people since March 2021. Kidney transplant recipients (KTRs) are at an increased risk of severe infection. Their outcomes appear to be worse than those in the general population. There is no robust evidence or consensus to support any form of treatment protocol or modification of immunosuppression in KTRs with COVID-19. There is a need to develop effective and safe therapeutic protocols for this frail population. Remdesivir is the only approved antiviral drug in COVID-19 till now. METHODS: We describe clinical features, role of HRCT, therapeutic protocols, and mortality rate of 20 KTRs with SARS-CoV-2 infection. RESULTS: Complete recovery was seen in 8 (40%) patients monitored at home. 12 (60%) patients with HRCT scores more than 8/25 were hospitalized. 11 (55%) had hypoxia, of these 8 (40%) had mild hypoxia, 1 (5%) required NIV, and 2 (10%) needed mechanical ventilation. Immunosuppression was modified in all the patients. Remdesivir and dexamethasone were administered to the hospitalized patients. 1 (5%) patient had AKI requiring RRT. 1 (5%) patient expired, and 1 still hospitalized. 10 of the hospitalized patients recovered. Out of the total 20 patients, 18 (90%) recovered completely within two weeks of infection. CONCLUSION: Clinical presentation of COVID-19 in KTRs was similar to nontransplant patients. Early hospitalisation and assessing the severity by HRCT were important. Continuing tacrolimus and administering remdesivir and dexamethasone reduced the incidence of renal failure and improved survival rates.

Severe Acute Respiratory Syndrome Corona Virus-2 Infection in a Pediatric Kidney Transplant Recipient: A Case Report from India.

COVID-19 pandemic affected millions of people across India. COVID-19 cases are fewer in children with less severity and better outcomes than in adults. However, a small proportion develop severe illness and succumb to the disease. Clinical manifestations and optimal management of COVID-19 in immunocompromised children are not clearly known. Remdesivir was shown to be efficient in reducing the recovery time in COVID-19 patients requiring supplemental oxygen. Remdesivir is approved for use in children with severe COVID-19, but there are no guidelines in patients with risk factors like recent solid organ transplantation. We report a case of a 10-year-old kidney transplant recipient (KTR) infected with severe acute respiratory syndrome corona virus-2, 2.5 months after the transplantation. Unlike most children, he presented with high fever, cough, and vomiting. His inflammatory markers were elevated. In this case report, we discussed management and clinical outcomes of this patient. In view of recent kidney transplantation and the severity of infection with emergent oxygen requirement, we gave him remdesivir. We continued prednisolone and tacrolimus and stopped mycophenolate. He recovered completely in 7 days. We feel that severely immunosuppressed KTR children with COVID-19 will benefit with remdesivir administration. Monitoring tacrolimus trough levels is essential for maintaining adequate immunosuppression.

Uncoupling the Folding and Binding of an Intrinsically Disordered Protein.

The relationship between helical stability and binding affinity was examined for the intrinsically disordered transactivation domain of the myeloblastosis oncoprotein, c-Myb, and its ordered binding partner, KIX. A series of c-Myb mutants was designed to either increase or decrease helical stability without changing the binding interface with KIX. This included a complimentary series of A, G, P, and V mutants at three non-interacting sites. We were able to use the glycine mutants as a reference state and show a strong correlation between binding affinity and helical stability. The intrinsic helicity of c-Myb is 21%, and helicity values of the mutants ranged from 8% to 28%. The c-Myb helix is divided into two conformationally distinct segments. The N-terminal segment, from K291-L301, has an average helicity greater than 60% and the C-terminal segment, from S304-L315, has an average helicity less than 10%. We observed different effects on binding when these two segments were mutated. Mutants in the N-terminal segment that increased helicity had no effect on the binding affinity to KIX, while helix destabilizing glycine and proline mutants reduced binding affinity by more than 1 kcal/mol. Mutants that either increased or decreased helical stability in the C-terminal segment had almost no effect on binding. However, several of the mutants reveal the presence of multiple conformations accessible in the bound state based on changes in enthalpy and linkage analysis of binding free energies. These results may explain the high level of sequence identity (>90%), even at non-interacting sites, for c-Myb homologues.

Conserved Helix-Flanking Prolines Modulate Intrinsically Disordered Protein:Target Affinity by Altering the Lifetime of the Bound Complex.

Appropriate integration of cellular signals requires a delicate balance of ligand-target binding affinities. Increasing the level of residual structure in intrinsically disordered proteins (IDPs), which are overrepresented in these cellular processes, has been shown previously to enhance binding affinities and alter cellular function. Conserved proline residues are commonly found flanking regions of IDPs that become helical upon interacting with a partner protein. Here, we mutate these helix-flanking prolines in p53 and MLL and find opposite effects on binding affinity upon an increase in free IDP helicity. In both cases, changes in affinity were due to alterations in dissociation, not association, rate constants, which is inconsistent with conformational selection mechanisms. We conclude that, contrary to previous suggestions, helix-flanking prolines do not regulate affinity by modulating the rate of complex formation. Instead, they influence binding affinities by controlling the lifetime of the bound complex.