How infection site affects the immune system

A new study by scientists at the Gladstone Institutes shows that infection sites could affect the immune system's response to a virus and the way the virus spreads through the body. The researchers focused on common routes of sexual transmission of viruses, such as the lower female reproductive tract and the lower gastrointestinal tract that includes the large intestine and the anus.

These mucosal barriers-the body's openings lined with a membrane called mucosa are responsible for distinguishing between harmless bacteria that normally reside in human and potentially dangerous pathogens, as well as other substances, such as food or sperm. Human body is constantly trying to balance between tolerating harmless elements and defending against the threats.

Reseachers discovered that the body's reaction is different based on the infection site. They showed that the vaginal and rectal cavities activate a distinct immune response to the same pathogen. To conduct the study, research team created a new model of viral infection through the rectum that uses lymphocytic choriomeningitis virus (LCMV), a rodent virus often used in research to model other pathogens. They then compared their findings to their previous work on vaginal infection by LCMV.

In 2016, they showed that vaginal infection causes a delayed response by protective cells. As a result, the immune system takes longer to clear the virus from the female reproductive tract. They also noticed that the virus stayed in the vagina and didn't spread to other parts of the body. In contrast, the new study indicates that, after infection through the rectum, the virus rapidly spreads throughout the body. The scientists also found that the virus wasn't being carried through the blood. Instead, LCMV infects the body's own immune cells, which in turn spread the virus systemically. Interestingly, this is the same dissemination process used by the HIV virus.

The initial immune response elicited depends on the route of infection, and can actually dictate the dissemination of the virus. The researchers revealed that mucosal barriers have different tolerance mechanisms that affect the immune system's response to invading pathogens. Once a virus breaches one of the barriers, early events in the body's response to that virus can play a key role in determining the outcome of an infection.
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How intestine repairs itself

Researchers at Baylor College of Medicine, Johns Hopkins University School of Medicine and the University of California, San Francisco have gained new insights into how the small intestine, one of the fastest renewing tissues in the human body, repairs itself after injury caused by intestinal rotavirus infection. Their findings have led them to propose that, contrary to the current thinking, how the intestine repairs itself seems to depend on the type of damage, and they found that triggers that were previously thought to be unimportant are actually essential for repairing virus-caused injury.

They studied different damage model, damage caused by rotavirus, a common small intestinal viral infection that affects young children. Repair and turnover of the epithelium, the most external cellular layer of the small intestine responsible for absorption of nutrients and other functions, depend on the intestinal stem cells, regardless of the cause of the damage. There are two types of intestinal stem cells: CBCs (crypt-based columnar cells) and reserve intestinal stem cells. The type of injuries studied until now damages the highly proliferative CBCs, and when these stem cells are destroyed, the reserve intestinal stem cells respond to restore the damage. The response to injury caused by rotavirus, however, is different.

Rotavirus is an infection and has a very specific damage pattern, the virus specifically infects epithelial cells, but not the stem cells. The first finding refers to the type of stem cell involved in the repair of the epithelial cells damaged by the virus. Previous studies had shown that when CBC stem cells are damaged, the reserve stem cells come to their rescue leading the reconstitution of the damaged epithelium. When rotavirus damages the epithelium, but not the stem cells,  the CBCs, not the reserve stem cells, are the primary cell type involved in the restoration of the intestinal epithelium.

 CBCs were not considered important for the repair of intestinal epithelium, but the results show that they are crucial for injury repair after rotavirus-induced epithelial cell damage in contrast to previous studies supporting the reserve intestinal stem cells as the cell type involved in epithelial restitution. The second finding refers to the source of the signaling molecules-called WNTs that trigger the growth and activation of stem cells leading to injury repair. Scientists have described two sources of WNT molecules, epithelial cells and mesenchymal cells. Epithelial WNT molecules were essential to signal the stem cells to repair the damage caused by rotavirus infection.
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Type 1 IFNs interfere Zika pregnancy complications

Researchers from the Yale University School of Medicine in New Haven examined the role of type 1 IFNs in limiting or mediating ZIKV disease within a model of congenital infection, observed after ZIKV infection of type I IFN receptor knockout ( ifnar1 −/− ) dams mating with wild-type sires, resulting in fetuses with functional type 1 IFN signaling.

Pregnant dams carried a mixture of fetuses that expressed or did not express IFN-α/β receptor (IFNAR) ( ifnar1+/− and ifnar1 −/− ) within the same uterus. The researchers found that the titer of virus replication was higher in the placenta of ifnar1 −/− than ifnar1 +/− . Only ifnar1 +/− fetuses were resorbed after ZIKV infection during early pregnancy; ifnar1 −/− littermates continued to develop.

IFNAR signaling in the conceptus was found to inhibit development of the placental labyrinth, resulting in abnormal maternal-fetal barrier architecture after ZIKV infection. Exposure of midgestation human chorionic villous explants to type I IFN resulted in altered placental morphology and cytoskeletal rearrangements within the villous core; this was not seen with exposure to type III IFN.

The results implicate type I IFNs as a possible mediator of pregnancy complications, including spontaneous abortions and growth restriction, in the context of congenital viral infections.
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Prevymn for intravenous infusion

 Food and Drug Administration FDA has approved Prevymis (letermovir) once-daily tablets for oral use and injection for intravenous infusion. Prevymis is indicated for prophylaxis (prevention) of cytomegalovirus CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant HSCT. CMV is a common and potentially serious viral infection in allogeneic HSCT recipients. CMV-seropositive patients who undergo an HSCT are at high risk for CMV reactivation. Any level of CMV infection is associated with increased mortality in HSCT patients.

 In this study, the incidence of bone marrow suppression in the Prevymis group was comparable to the placebo group. The median time to engraftment was 19 days in the Prevymis group and 18 days in the placebo group. Prevymis is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations may lead to ergotism.

Prevymis is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis. The concomitant use of Prevymis (letermovir) and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (Prevymis or concomitant drugs) or reduced therapeutic effect of Prevymis or the concomitant drug.

 Consider the potential for drug interactions prior to and during Prevymis therapy; review concomitant medications during Prevymis therapy; and monitor for adverse reactions associated with Prevymis and concomitant medications.This findings demonstrate that letermovir is a significant and welcomed advance in the prevention of clinically significant CMV infection and lowers mortality in this highly vulnerable patient population.

The recommended dosage of Prevymis is 480 mg administered once daily, initiated as early as Day 0 and up to Day 28 post-transplantation (before or after engraftment), and continued through Day 100 post-transplantation. If Prevymis is co-administered with cyclosporine, the dosage of oral or intravenous Prevymis should be decreased to 240 mg once daily. Prevymis is available as 240 mg and 480 mg tablets, which may be administered with or without food. Prevymis is also available as 240 mg and 480 mg injection for intravenous infusion via a peripheral catheter or central venous line at a constant rate over one hour.
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Strong persistence of viral infection

Infections caused by viruses, such as respiratory syncytial virus, measles, parainfluenza and Ebola, are acute. These viruses cause disease quickly and live within a host for a limited time. But in some cases the effects of the infection, and presence of the virus can lead to chronic problems.

Viral infection leads to defective viral genomes, DVG which involved in triggering an immune response, can also kick off a molecular pathway that keeps infected cells alive. The study used a novel technique to examine the presence of DVGs on a cell-by-cell basis to show that DVG-enriched cells had strategies to survive during an immune-system attack.

Partial viral genomes are produced in infected cells when a virus begins to replicate rapidly, leading to defective versions that contain large deletions. DVGs are increasingly believed to be important components of viral infections.

DVGs are critical in stimulating an immune response to respiratory viruses, they are also critical for stimulating an immune response to the human virus RSV, the presence of DVGs in human respiratory samples from infected patients correlates with enhanced antiviral immune responses.

Researchers used a sophisticated technique that allowed them to differentiate full-length genomes from the partial genomes of DVGs at the single-cell level. They studied cells in culture infected with the Sendai virus, or with RSV, a virus that often affects infants and can lead to chronic respiratory problems.

To dig deeper into how the DVGs were influencing the course of infection, the researchers infected cells either with a version of the Sendai virus that lacked DVGs or one enriched in DVGs. The cells infected with the virus high in DVGs survived more than twice as long as those infected with virus lacking DVGs.

 Adding purified DVGs boosted the cells' survival time, indicating a direct role for the DVGs in promoting cell survival.
The results were similar in parallel experiments with RSV, suggesting that the pro-survival role of DVGs held across viral types.

The researchers next were curious to know what molecular pathways might enable the DVG-rich cells to avoid apoptosis. An analysis of highly-expressed genes in DVG-enriched cells compared to the cells with full-length viral genomes revealed that a host of pro-survival genes were activated in the DVG-rich cells.
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Vosevi drug for hepatitis treatment

Hepatitis C is a viral infection that can cause inflammation and serious damage to the liver. The virus is spread through human contact with infected blood.

The U.S. Food and Drug Administration (FDA) has approved Vosevi (sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg) tablets, a single-tablet regimen for the treatment of adults with chronic hepatitis C virus (HCV).

Vosevi is a prescription medicine used to treat adults with chronic (lasting a long time) hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis who have:
genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor.

Do not combine Vosevi with any medicines that contain rifampin (Rifater, Rifamate, Rimactane, Rifadin).
Before taking Vosevi

The drug can cause serious side effects, like: Hepatitis B virus (HBV) reactivation, slow heart rate, fainting,
dizziness, shortness of breath, chest pains, confusion, memory problems, headache, tiredness, diarrhea, and nausea.
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