Newswise — Infections can manifest in various ways, but a prevalent symptom is the depletion of fat and muscle, known as wasting. Researchers at the Salk Institute aimed to investigate the potential benefits of wasting in combating infections.
Within Professor Janelle Ayres’ lab, scientists made a noteworthy discovery concerning the wasting response to T. brucei infection in mice. This response occurs in two distinct phases, each controlled by different immune cells. Surprisingly, while the loss of fat did not contribute to the fight against infection, the loss of muscle did. This finding suggests that certain types of wasting might actually aid in managing illness.
The results of this study, which were published in Cell Reports on July 24, 2023, hold promise for developing more effective therapeutics that can spare individuals from wasting. Moreover, this research deepens our comprehension of how wasting influences survival and morbidity across various conditions, such as infections, cancers, chronic illnesses, and beyond.
"We often jump to assumptions that conditions like wasting are inherently negative, given their association with higher mortality rates," explains senior author Ayres, holding the Salk Institute Legacy Chair and leading the Molecular and Systems Physiology Laboratory. "However, if we shift our perspective and ask ourselves, what purpose does wasting serve? We might uncover surprising and profound insights that enhance our understanding of how the human body responds to infections and how we can optimize this response."
Defending the body against invaders demands substantial energy. Previous studies implied that this immune-related energy consumption resulted in wasting as an unfortunate consequence. Nevertheless, Ayres and the research team were driven by curiosity to explore whether wasting could hold beneficial properties rather than being merely a side effect.
Their focus turned to specialized immune cells known as T cells, which exhibit a slower response to infections but eventually adapt to combat the specific invader. Ayres sought to investigate whether these T cells were responsible for the occurrence of wasting. If T cells indeed played a role in the condition, it would indicate that wasting is not merely an unproductive side effect of energy-hungry immune cells. Instead, it might have a distinct purpose in the body's immune defense mechanisms.
The cells under investigation are known as CD4+ and CD8+ T cells. CD4+ T cells play a leading role in combating infections and can enhance the activity of CD8+ T cells, which are responsible for eliminating invaders and cancerous cells. These two types of T cells often collaborate, leading the researchers to speculate that their involvement in wasting might also be a cooperative effort.
To explore the connection between CD4+ and CD8+ T cells and wasting, the researchers focused on the parasite T. brucei. This parasite resides in fat and can impede the adaptive immune response, which includes T cells, making it an ideal model for studying fat wasting and the role of T cells in mediating this process.
Their investigation centered around two main objectives: 1) understanding the contributions of CD4+ and CD8+ T cells during T. brucei infection, and 2) examining the effects of removing CD4+ and CD8+ T cells on the lifespan, mortality rates, parasite symptoms, and parasite levels in infected mice.
The findings revealed that CD4+ T cells took the lead and triggered the process of fat wasting. Subsequently, but independently from fat wasting, CD8+ T cells initiated muscle wasting. Surprisingly, the fat wasting induced by CD4+ T cells had no impact on the mice's ability to fight T. brucei or survive the infection. On the other hand, contrary to conventional assumptions about wasting, the muscle wasting induced by CD8+ T cells actually aided the mice in combating T. brucei and surviving the infection.
"Our discoveries left us so astonished that at times, I questioned whether we had made mistakes," admits first author Samuel Redford, presently a visiting researcher and a former graduate student in Professor Ayres' lab. "We obtained remarkable results, showing that mice with fully functional immune systems and mice lacking CD4+ T cells lived for the same duration—implying that these CD4+ T cells and the fat wasting they caused were entirely dispensable in the fight against the parasite. Moreover, we uncovered that typically cooperative T cell subtypes were operating completely independently of each other."
These findings highlight the crucial role of immune cells in both fat and muscle wasting, underscoring the importance of understanding such responses for developing effective therapeutic interventions.
"We can gain invaluable insights into our immune systems by studying the environments and infections that have co-evolved with us," explains Ayres. "While T. brucei serves as a captivating and significant case, what truly excites us is the ability to extend our findings to comprehend, treat, and overcome any disease involving immune-mediated wasting—be it parasites, tumors, chronic illnesses, and beyond."
In the future, the research team plans to investigate the T cell mechanisms in other mammals and, eventually, in humans. Additionally, they aim to delve deeper into understanding the underlying reasons for muscle wasting and the distinct roles played by CD4+ and CD8+ T cells in this process. Through these endeavors, they hope to unravel further mysteries and pave the way for innovative approaches to combat various diseases associated with wasting.
“Number needed to vaccinate with a COVID-19 booster to prevent a COVID-19-associated hospitalization during SARS-CoV-2 Omicron BA.1 variant predominance, December 2021-February 2022, VISION Network: a retrospective cohort study” is published in The Lancet Regional Health–Americas.
Regenstrief Institute co-authors, in addition to Dr. Grannis, are Interim Director of the Center for Biomedical Informatics Brian Dixon, PhD, MPA; William F. Fadel, PhD and Nimish R. Valvi, DrPH. Peter Embí, M.D., former president of the Regenstrief Institute and current affiliated scientist, is also a co-author.
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