Anyone who’s ever had the flu or a bad cold can relate to the lethargy, sleepiness, and an increased sensitivity to pain that often result when a pathogen infects a host. A Salk Institute study, published January 26 in Cell, looked at one of the most well-known sickness behaviors–loss of appetite–in mice and found, surprisingly, that when a bacteria reduces its own virulence (how sick it makes the host) by blocking this anorexic response, it actually increases mouse survival and helps the pathogen spread because more food means more infected feces.

“Traditionally in infectious disease, we think that the stronger a pathogen’s ability is to cause disease, the greater its potential is to be transmitted to other hosts,” says senior author Janelle Ayres, an assistant professor in immunobiology and microbial pathogenesis at the Salk Institute for Biological Studies. “But we discovered a pathogen that has evolved to become less dangerous to its host. By employing this strategy, it’s easier for the pathogen to spread to other hosts.”

In the study, the investigators looked at Salmonella Typhimurium, a natural intestinal pathogen in mice (as well as humans) that can easily be transmitted to new hosts. Previous work looking at the connection between Salmonella and loss of appetite has mostly involved injecting a microbe or microbial products directly into the circulation of an animal model and studying its effect, but Ayres’ group infected the animals orally–thus mimicking the bacteria’s route of infection (it spreads from mouse to mouse when the animals eat each other’s contaminated feces).

“Host response is only half of the infectious disease equation. We wanted to understand how the bacteria’s behavior is affected by the host’s loss of appetite, as well,” Ayres says. “What a pathogen wants is a steady supply of nutrients, a stable niche so it can replicate, and a reliable mode of transmission.” In this case, taming the behavior of the pathogen by enabling the mice to take in more nutrition helped keep the mouse healthy, produce more feces, and then spread infection to other animals.

Further investigation revealed the mechanism by which Salmonella Typhimurium inhibits loss of appetite. Sickness behaviors are in large part mediated by a cytokine–a type of molecule involved in cell-to-cell communication–that sends a signal to the hypothalamus, a region of the brain controlling appetite. But this particular Salmonella blocks activation of the cytokine in the intestines, preventing the gut from signaling to the brain.

Ayres says she anticipates finding a similar strategy in other microbes, noting that genes similar to the one known to be important in blocking cytokine activation in SalmonellaTyphimurium also are found in other pathogens. “But a more interesting place to look is at the components of the microbiome, especially the human microbiome,” she notes.

“When an infection in the host affects appetite, the microbiome is also potentially compromised by the loss of nutrition. I expect to find that the microbiome has evolved strategies to block this sickness response,” Ayres adds.

This is something her research group plans to study.

The researchers hope that one day, their findings may lead to a better understanding of infection transmission and new ways to treat infections by supplementing patients with nutrition rather than treating them with antibiotics. The goal would be to give patients a treatment that would also prevent them from spreading their cold or fever to others.

For the first time, a multicomponent virus–which contains different segments of genetic material in separate particles, rather than a single strand of genetic material–has been found that is capable of infecting animals, an international team led by the U.S. Army reports August 25 in Cell Host & Microbe. The Guaico Culex virus (GCXV), a type of Jingmenvirus, was isolated from mosquitoes, and opens up a new avenue of research into potentially infectious agents. The virus does not appear to infect mammals.

“Until now, multicomponent viruses were thought to infect only plants and fungi, as a result of relatively inefficient transmission,” says first author Jason Ladner, a staff scientist from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). “Our finding that these viruses are present in mosquitoes is going to challenge us to re-evaluate some of our assumptions about them.”

Multicomponent viruses use a method of transmission that’s different from other viruses known to infect animals. Instead of being contained in a single viral particle, their genomes are segmented and encapsulated among multiple particles. A yellow fever virus, for example, has all its genetic material packaged into a single particle. Therefore, one particle is enough to infect a cell. But in order for a multicomponent virus to establish an infection, the cell has to get infected with at least one particle of each type.

The research is part of a global effort to monitor and prepare for outbreaks of unknown viral diseases. Mosquitoes and other insects can act as vectors for viral diseases, carrying them from place to place and transmitting them to human hosts via bites. Although the new virus does not appear to be a human pathogen, or even a mammalian one, the investigators say this work is a good exercise to help hone the tools and expertise needed to characterize novel infectious agents.

In the study, the USAMRIID researchers worked with several other teams, including groups from the University of Texas Medical Branch and the New York State Department of Health, to isolate mosquitoes from different regions around the world. The newly discovered virus is named Guaico Culex after the Guaico region of Trinidad in which the mosquitoes that contained it were found.

Guaico Culex was isolated by growing material obtained from the mosquitoes in cell culture. “This method has been useful particularly in finding new arboviruses, which are transmitted by mosquitoes and other arthropods to mammals,” Ladner says. To identify arboviruses, cultures of mammalian cells are used. “We were also interested in viruses that may be found within mosquitoes but don’t necessarily grow on mammalian cells, so we used cultures of insect cells, enabling us to find this new virus.”

Deep sequencing indicated that Guaico Culex belongs to a group of segmented viruses called Jingmenviruses, which were first discovered in 2014. In collaboration with a group at the University of Wisconsin-Madison, the USAMRIID researchers also showed for the first time evidence of a Jingmenvirus in the blood of a non-human primate, in this case a Ugandan red colobus monkey. This finding is also published in the current Cell Host & Microbe paper.

Experts believe that the most likely infectious viruses to make the jump to humans are those that are already circulating in other mammals, especially non-human primates. Phylogenetic analysis indicated that this monkey virus shared a segmented common ancestor with Guaico Culex. However, researchers don’t yet know if all Jingmenviruses are multicomponent like the Guaico Culex virus. It is also not known whether the Jingmenvirus isolated from the monkey had a pathogenic effect.

“One of the things we’re focused on at USAMRIID is rapid identification of pathogens from both clinical and environmental samples as well as characterization of novel viruses,” says Gustavo Palacios, Director of the Center for Genome Sciences at USAMRIID and the study’s senior author. “We’re trying to make sure that we’re not blindsided when the next virus comes around. With all of the diversity seen in these emerging viruses, we never know what the next one will be to have an impact on human health.”

A new study puts some old folk wisdom to “feed a cold and starve a fever” to the test. In mouse models of disease, Yale researchers looked at the effects of providing nutrients during infection and found opposing effects depending on whether the infections were bacterial or viral. Mice with bacterial infections that were fed died, while those with viral infections who were fed lived. The paper appears September 8 in Cell.

“We were surprised at how profound the effects of feeding were, both positive and negative,” says senior author Ruslan Medzhitov, David W. Wallace Professor of Immunobiology and a Howard Hughes Medical Institute investigator at Yale School of Medicine. “Anorexia–not eating–is a common behavior during sickness that is seen in people and all kinds of animals. Our findings show that it has a strong protective effect with certain infections, but not with others.”

In the first series of experiments, the investigators infected mice with the bacterium Listeria monocytogenes, which commonly causes food poisoning. The mice stopped eating, and they eventually recovered. But when the mice were force fed, they died. The researchers then broke the food down by component and found fatal reactions when the mice were given glucose, but not when they were fed proteins or fats. Giving mice the chemical 2-DG, which prevents glucose metabolism, was enough to rescue even mice who were fed glucose and allowed them to survive the infection.

When the researchers did similar studies in mice with viral infections, they found the opposite effect. Mice infected with the flu virus A/WSN/33 survived when they were force fed glucose, but died when they were denied food or given 2-DG.

Further research showed that different areas of the brain were affected depending on which type of infection the mice died from, indicating that the animals’ metabolic needs differ depending on which part of the immune system had been activated.

“Almost everything we know about infection is based on immune response studies and looking at how the immune system eliminates pathogens,” Medzhitov says. “But that’s not the only way we defend ourselves. There are also cases where we change and adapt so that microbes don’t cause harm. Our study manipulated the ability of these mice to tolerate and survive infection without doing anything that had an effect on the pathogens themselves.”

Medzhitov’s Lab is now looking at the effects of another common sickness behavior–changes in sleep patterns–on how the immune system fights infection. His team is also doing follow-up studies on the pathways involved in food preference, which may explain the cravings that people have for certain foods when they’re sick.

But he says their findings may have more immediate implications as well, for the design of clinical trials evaluating the benefits of providing nutrients to patients with sepsis. “Sepsis is a critical problem in hospital ICUs that defies most modern medical approaches,” he says. “A number of studies have looked at nutrition in patients with sepsis, and the results have been mixed. But these studies didn’t segregate patients based on whether their sepsis was bacterial or viral. The implication is that patients should be stratified by the cause of their sepsis, and trials should be designed based on that.”

The itchy, red welts that appear after being bitten by a mosquito may help any viruses the insect is carrying pass on to a new host. A mouse study published June 21 in Immunity suggests that the swelling and irritation that make mosquito bites so unpleasant may provide a mechanism by which viruses like Zika are able to replicate and spread.

“Before we did this study, little was known about the events and processes that occur at mosquito bite sites,” says Clive McKimmie, a Research Fellow at the University of Leeds and the paper’s senior author. “Our findings suggest that the inflammatory response at these sites helps viruses to replicate, enhancing their ability to cause disease.”

In the new research, the investigators used mouse models to study the bites of the Aedes aegypti mosquito, the species that spreads infections such as Zika, dengue, and chikungunya.

When a mosquito bites, it injects saliva into the skin. The saliva triggers an immune response, in which white blood cells called neutrophils and myeloid cells rush to the site. In this study, the team injected mice with viruses into the skin with or without the presence of a mosquito bite at the injection site and compared the reaction. They found that instead of helping, some of these immune cells get infected and inadvertently replicate virus.

In the absence of mosquito bites and their accompanying inflammation, the viruses failed to replicate well. But the presence of mosquito bites at the infection site resulted in an order of magnitude higher levels of virus. Further studies showed that the influx of white blood cells was required for enhanced replication of the viruses.

According to McKimmie, previous studies that have used in vivo models to study the course of mosquito-borne infections haven’t looked at the bite as a necessary component. “We think the bite itself is affecting the systemic course and clinical outcome of the infection,” he says. “If you want an in vivo model that replicates the most relevant parts of infection, you should include this inflammatory aspect.”

“This was a big surprise we didn’t expect,” he adds. “These viruses are not known for infecting immune cells. And sure enough, when we stopped these immune cells from coming in, the bite did not enhance the infection anymore.”

Although this research is still early work done in mice, McKimmie says the finding suggests new approaches for combating viruses that lead to health problems in humans. “We’re quite keen to see if using topical creams to suppress bite inflammation will enable you to stop a virus from making someone as sick as it otherwise would do,” he says.

He notes that if it’s proven effective, this approach could work against future virus outbreaks that we don’t know about yet. “Nobody expected Zika, and before that nobody expected chikungunya,” he says. “There are estimated to be hundreds of other mosquito-borne viruses out there and it’s hard to predict what’s going to start the next outbreak.”