Functional classification of memory CD8(+) T cells by CX(3)CR1 expression

Localization of memory CD8(+) T cells to lymphoid or peripheral tissues is believed to correlate with proliferative capacity or effector function. Here we demonstrate that the fractalkine-receptor/CX(3)CR1 distinguishes memory CD8(+) T cells with cytotoxic effector function from those with proliferative capacity, independent of tissue-homing properties. CX(3)CR1-based transcriptome and proteome-profiling defines a core signature of memory CD8(+) T cells with effector function. We find CD62L(hi)CX(3)CR1(+) memory T cells that reside within lymph nodes. This population shows distinct migration patterns and positioning in proximity to pathogen entry sites. Virus-specific CX(3)CR1(+) memory CD8(+) T cells are scarce during chronic infection in humans and mice but increase when infection is controlled spontaneously or by therapeutic intervention. This CX3CR1-based functional classification will help to resolve the principles of protective CD8(+) T-cell memory

Infection with hepatitis B virus carrying novel pre-S/S gene mutations in female siblings vaccinated at birth: two case reports

<p>Abstract</p> <p>Introduction</p> <p>After the initiation of a mass hepatitis B vaccination program in Taiwan, the prevalence of hepatitis B virus infection has declined progressively. However, about 1 percent of the young generation, who received hepatitis B vaccination at birth, remain carriers. Infection with vaccine-escape hepatitis B virus mutants always occurs shortly after birth. Here, we report two female siblings in whom the infection occurred in their adolescence. This report raises the question of whether a booster for hepatitis B vaccination is needed.</p> <p>Case presentation</p> <p>Two 19 and 14-year-old Taiwanese female siblings were born to a mother infected with hepatitis B virus and received a complete course of hepatitis B vaccination at birth. They remained negative for serum hepatitis B surface antigen and positive for serum anti-hepatitis B surface antibody throughout their childhood. However, both were infected with the hepatitis B virus in their adolescence. Hepatitis B virus DNA was extracted from serum samples from the mother and two siblings. Hepatitis B virus pre-S/S sequence was amplified by polymerase chain reaction followed by nucleotide sequencing. When compared with the sequence obtained from the mother, multiple amino acid substitutions located near or in the major hydrophilic region of the surface antigen were identified in the elder sister. Four of these mutations (sL97S, sL98S, sG102R, and sA159P) were novel. A novel in-frame deletion (14 amino acids deleted, pre-S 127-140) was found in the hepatitis B virus pre-S2 region in the younger sister.</p> <p>Conclusions</p> <p>Despite having received hepatitis B vaccination at birth, hepatitis B virus infection can still occur in adolescence with the emergence of novel mutations in the pre-S/S gene. This is a rare event and, to the best of our knowledge, has not been previously reported.</p

Living in the liver: Hepatic infections.

The liver has vital metabolic and clearance functions that involve the uptake of nutrients, waste products and pathogens from the blood. In addition, its unique immunoregulatory functions mediated by local expression of co-inhibitory receptors and immunosuppressive mediators help to prevent inadvertent organ damage. However, these tolerogenic properties render the liver an attractive target site for pathogens. Although most pathogens that reach the liver via the blood are eliminated or controlled by local innate and adaptive immune responses, some pathogens (such as hepatitis viruses) can escape immune control and persist in hepatocytes, causing substantial morbidity and mortality worldwide. Here, we review our current knowledge of the mechanisms of liver targeting by pathogens and describe the interplay between pathogens and host factors that promote pathogen elimination and maintain organ integrity or that allow pathogen persistence

Montelukast is a dual-purpose inhibitor of SARS-CoV-2 infection and virus-induced IL-6 expression identified by structure-based drug repurposing.

Drug-repurposing has been instrumental to identify drugs preventing SARS-CoV-2 replication or attenuating the disease course of COVID-19. Here, we identify through structure-based drug-repurposing a dual-purpose inhibitor of SARS-CoV-2 infection and of IL-6 production by immune cells. We created a computational structure model of the receptor binding domain (RBD) of the SARS-CoV-2 spike 1 protein, and used this model for in silico screening against a library of 6171 molecularly defined binding-sites from drug molecules. Molecular dynamics simulation of candidate molecules with high RBD binding-scores in docking analysis predicted montelukast, an antagonist of the cysteinyl-leukotriene-receptor, to disturb the RBD structure, and infection experiments demonstrated inhibition of SARS-CoV-2 infection, although montelukast binding was outside the ACE2-binding site. Molecular dynamics simulation of SARS-CoV-2 variant RBDs correctly predicted interference of montelukast with infection by the beta but not the more infectious alpha variant. With distinct binding sites for RBD and the leukotriene receptor, montelukast also prevented SARS-CoV-2-induced IL-6 release from immune cells. The inhibition of SARS-CoV-2 infection through a molecule binding distal to the ACE-binding site of the RBD points towards an allosteric mechanism that is not conserved in the more infectious alpha and delta SARS-CoV-2 variants

Transfer of HBV genomes using low doses of adenovirus vectors leads to persistent infection in immune competent mice.

Studies of mechanisms responsible for the persistence of hepatitis B virus (HBV) infection have been hindered by a lack of appropriate animal models. HBV genomes can be delivered to livers of mice using hydrodynamic injection or high doses of an adenoviral vector; these lead to clearance of HBV. We found that infection of immunocompetent mice with low doses of an adenoviral vector resulted in persistent HBV infection; the mice neither underwent seroconversion to production of antibodies against HBV nor developed a strong HBV-specific effector T-cell response. As in patients with chronic HBV infection, DNA vaccination failed to generate T cells that cleared infection. This model of persistent HBV infection could be used to study the pathogenesis of chronic HBV infection and develop new therapeutic strategies