Infections can present with many different symptoms, and one common symptom is wasting, which involves the loss of fat and in extreme cases lean muscle as well. Researchers in the lab of Salk Institute professor Janelle Ayres, PhD, have now found that in mice, wasting response to infection by the parasite Trypanosoma brucei—the causative agent of sleeping sickness—occurs in two phases, each regulated by different immune cells. Their study results showed that during T. brucei infection, it is CD4+ T cells that play a role in the development of sickness-induced anorexia and fat wasting, while CD8+ T cells are linked with cachexia. The findings also suggested that while fat loss did not benefit the fight against infection, muscle loss dida surprising clue that some wasting may help manage illness.

The study results might help to inform the future development of more effective therapeutics that spare people from wasting, as well as increase understanding of how wasting influences survival and morbidity across infections, cancers, chronic illnesses, and other disorders. “We often make assumptions that conditions like wasting are bad, since they often coincide with higher mortality rates,” said Ayres, Salk Institute Legacy Chair and head of the Molecular and Systems Physiology Laboratory. “But if instead we ask, what is the purpose of wasting? We can find surprising and insightful answers that can help us understand the human response to infection and how we can optimize that response.” Ayers is senior author of the team’s published paper in Cell Reports, which is titled “CD4+ T cells regulate sickness-induced anorexia and fat wasting during a chronic parasitic infection.”

Infections cause reprogramming of host metabolic processes, the authors explained, and clinically, the most obvious metabolic response to infection is energy stores wasting. Cachexia is what the team describes as “an extreme catabolic state,” and is characterized by unintentional weight loss and muscle loss, which can include fat loss. Wasting in which there is only fat loss is known as adipose tissue wasting. However, the team continued, “Whether cachexia or adipose tissue wasting serves functional roles during infections remains unknown, but they are both typically viewed as maladaptive consequences of host-pathogen interactions.”

Defending the body from an invading pathogen takes a lot of energy, and will require what the investigators describe as “trade-offs with other biological functions.” Prior studies have suggested that this immune-related energy consumption has wasting as an unfortunate side effect. Ayres and team were curious to know whether wasting could be beneficial, and not just a side effect.

Trypanosoma brucei parasites (dark blue) among mouse blood cells
Trypanosoma brucei parasites (dark blue) among mouse blood cells (light blue and white). [Salk Institute]

T cells are immune cells that are relatively slow to respond to infections, but when they do respond, they adapt to fight the particular infection. Ayres was interested to know whether it was these T cells causing wasting. If T cells are responsible for the condition, that would indicate wasting is not simply an unproductive side effect of energy-hungry immune cells.

Of particular interest to the researchers were CD4+ and CD8+ T cells. CD4+ T cells lead the fight against infection and can promote the activity of CD8+ T cells, which can kill invaders and cancerous cells. The two T cell types often work together, so the team hypothesized their role in wasting may be a cooperative effort, too. “A better understanding of the roles of CD4+ and CD8+ T cells in regulating energy stores and how this relates to their functions in host defense is necessary,” they pointed out.

To work out the association between CD4+ and CD8+ T cells and wasting, the researchers studied infection with the parasite T. brucei, which resides in fat and can block the adaptive immune response, which includes T cells. This represented an ideal infection to address questions about fat wasting and how T cells mediate that process. “… we utilized a T. brucei-mouse infection model to investigate the role of the adaptive immune response in adipose tissue wasting and cachexia and to determine what function these catabolic responses have for host defense,” they commented. Using this model, the team investigated the role of CD4+ and CD8+ T cells during T. brucei infection in mice, and also assessed how removal of CD4+ and CD8+ T cells changed the longevity, mortality rates, parasite symptoms, and parasitic burden in infected animals.

From left: Janelle Ayres, Siva Varanasi, Karina Sanchez, Samuel Redford, and Natalia Thorup.
From left: Janelle Ayres, Siva Varanasi, Karina Sanchez, Samuel Redford, and Natalia Thorup. [Salk Institute]

The studies showed that in T. brucei infected mice, CD4+ T cells acted first and initiated the process of fat wasting. Afterward, but completely independently of fat wasting, CD8+ T cells initiated the process of muscle wasting. “We find that the wasting response occurs in two phases,

with the first stage involving fat wasting caused by CD4+ T cell-induced anorexia and a second anorexia-independent cachectic stage that is dependent on CD8+ T cells,” the investigators wrote. “We demonstrate that CD4+ T cells are drivers of adipose tissue wasting in response to T. brucei infection. We further demonstrate that CD4+ T cells are required for the induction of the sickness-induced anorexic response.”

Interestingly, CD4+ T cell-induced fat wasting had no impact on the ability of the mice to fight T. brucei or to survive infection. The CD8+ T cell-induced muscle wasting, however— and contrary to traditional assumptions about wasting – helped the mice fight T. brucei and survive the infection. “Fat wasting has no impact on host antibody-mediated resistance defenses or survival, while later-stage muscle wasting contributes to disease-tolerance defenses,” the team further noted. “Thus, at least in a murine model of T. brucei infection, adipose tissue wasting serves no apparent beneficial function for the host or the pathogen, while cachexia may contribute to host disease-tolerance defenses.”

“Our discoveries were so surprising that there were times I wondered if we did something wrong,” said first author Samuel Redford, PhD, a current visiting researcher and former graduate student in Ayres’ lab. “We had striking results that mice with fully functioning immune systems and mice without CD4+ T cells lived the same amount of time—meaning, those CD4+ T cells and the fat wasting they caused were completely disposable in fighting the parasite. And beyond that, we found that normally cooperative T cell subtypes were working totally independently of one another.”

The findings illustrate the important role of immune cells in both fat and muscle wasting and the necessity to understand the function of such responses to inform therapeutic interventions. “We can learn so much about our immune systems by looking at the environments and infections we have co-evolved with,” commented Ayres. “While T. brucei is an interesting and important case, what is exciting is extrapolating our findings to understand, treat, and overcome any disease that involves immune-mediated wasting—parasites, tumors, chronic illnesses, and so much more.”

Noting limitations of their study, the team noted in their summary, “We establish a role for CD4+ T cells in the development of sickness-induced anorexia and adipose tissue wasting and for CD8+ T cells in the development of muscle wasting and decouple these metabolic responses from host resistance defenses and instead suggest that muscle wasting may be important for promoting disease-tolerance defenses in some infection contexts.”

In the future, the team will examine the T cell mechanism in other mammals and eventually humans. They also want to explore in more detail why muscle wasting is occurring and why CD4+ and CD8+ T cells play these distinct roles.

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