Researchers have described the molecular mechanisms of cachexia during viral infection

Many patients with chronic illnesses such as AIDS, cancer and autoimmune diseases suffer from an additional disease called cachexia.

The complex, still poorly understood syndrome, with uncontrollable weight loss and shrinkage of both fat reserves and muscle tissue, is thought to contribute to premature death.

Researchers at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have described the molecular mechanisms of cachexia during viral infection and identify a surprising role for immune cells.

Cachexia is a multifactorial syndrome that occurs in patients suffering from chronic infections such as HIV, tuberculosis and malaria.

In addition, 50 percent to 80 percent of cancer patients are affected by cachexia.

Due to reduced food intake and altered metabolism, patients lose body weight and become physically weak.

Their fat reserves and skeletal muscle mass are progressively depleted, which cannot be reversed by nutritional supplementation.

Cachexia severely impacts the patient’s quality of life and worsens the outcome of ongoing therapies.

Despite urgent clinical need, the standards of diagnosis and care for cachectic patients remain insufficient and effective treatment options are elusive so far.

In recent years, studies using experimental models of cancer-associated cachexia greatly improved the understanding of how inflammation triggers cachexia and the associated metabolic alterations.

These studies showed that secreted inflammatory factors can induce weight loss through either direct or indirect mechanisms that affect appetite and alter fat and muscle metabolism.

The role of infectious diseases in developing cachexia lags, and researchers do not understood whether the same or different mechanisms of cachexia occur during infection and cancer.

The research group of Andreas Bergthaler, Principal Investigator at CeMM, together with collaboration partners from the University of Graz, the Medical University of Vienna as well as international collaboration partners from Germany, Switzerland and the U.S. elucidated a novel mechanism whereby chronic viral infection leads to cachexia.

These results are published in Nature Immunology and describe the organism-wide pathophysiological changes associated with cachexia during chronic viral infection.

By using well-controlled animal infection models, the researchers identified the key molecular players that lead to cachexia.

Viral infection resulted in a reduction of body weight.

This weight loss could only partially be explained by decreased food intake, and was not prevented by nutritional supplementation.

The researchers demonstrated that the viral infection led to a severe reorganization of the architecture of the fat tissue, which coincided with the activation of lipolysis, a molecular cascade of processes that the body uses to hydrolyze its fat depots.

Yet none of the inflammatory mediators known to induce cachexia in cancer seemed to play an important role during infection.

“This came as quite a surprise to us,” says first-author of the study, Ph.D. student Hatoon Baazim.

The researchers continued to study other potential mechanisms and realized that CD8 T cells were triggering cachexia. CD8 T cells are important immune system cells, which are able to recognize and kill virus-infected cells or cancer cells.

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Although there is no single universally agreed upon definition of cachexia, a recent consensus statement states that cachexia is a complex metabolic syndrome associated with underlying illness, and is characterized by the loss of muscle with or without loss of fat mass.

Cachexia is seen in many medical conditions, including cancer, acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease, multiple sclerosis, chronic heart failure, tuberculosis, familial amyloid polyneuropathy, mercury poisoning (acrodynia) and hormonal deficiency[1,2].

Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass, with or without wasting of adipose tissue[3].

Clinically, cachexia is represented by significant weight loss in adults and failure to thrive in children[4], accompanied by alterations in body composition and a disturbed balance of biological systems[5–7].

Whilst the loss of skeletal muscle mass is the most obvious symptom of cancer cachexia, cardiac muscle is also depleted, though muscle of other visceral organs tend to be preserved.

Though cachexia is seen in several disease states, the loss of muscle mass has been shown to occur most rapidly in cancer patients[8].

Cancer cachexia is an insidious syndrome that not only has a dramatic impact on patient quality of life, but is also associated with poor responses to chemotherapy and survival[9–11].

Indeed, cachexia occurs in the majority of terminal cancer patients and, according to Warren, is responsible for the death of 22% of cancer patients[12,13].

Current therapies focus on palliation of symptoms and the reduction of distress of patients and families rather than cure[14].

In many cases, cachexia remains a largely underestimated and untreated condition[4,15].

Approximately half of all patients with cancer experience cachexia[16,17], with the prevalence rising as high as 86% in the last 1-2 wk of life[18,19], and with 45% of patients lose more than 10% of their original body weight over the course of their disease progression[19].

Death usually occurs when there is 30% weight loss[5].

The best management strategy of cancer cachexia is to treat the underlying cancer as this will completely reverse the cachexia syndrome.

Unfortunately, this remains an infrequent achievement with advanced cancers.

A second option could be to counteract weight loss by increasing nutritional intake, but since in the majority of cachectic patients anorexia is only a part of the problem, nutrition as a unimodal therapy has not been able to completely reverse the wasting associated with cachexia.

CANCER CACHEXIA AND MALIGNANT INFLAMMATION

Multiple mechanisms are involved in the development of cachexia, including anorexia, decreased physical activity, decreased secretion of host anabolic hormones, and an altered host metabolic response with abnormalities in protein, lipid, and carbohydrate metabolism[20].

Due to the complex clinical findings, guidelines for the diagnosis of cachexia have just recently started to appear[3].

Even so, there is great variation in definitions, which presents problems when comparing studies and informing clinical diagnoses[21,22] (Table ​(Table11).

Table 1
Cancer cachexia

Treatment	Description	Physiologic benefit	Possible mechanism	Ref.
Megestrol acetate	Active progesterone derivative	Improves appetite, caloric intake, nutritional status, quality of life	Unknown; possible neuropeptide Y release	[80-92]
Medroxyprogesterone	Active progesterone derivative	Improves appetite, food intake Weight stabilization	Decreases serotonin, IL-1, IL-6, TNF-α	[93-96]
Ghrelin	Gastric peptide hormone	Improves lean + total body mass, hand grip, cardiac function (CHF cachexia only)	Growth hormone receptor secretagogue	[105]
Delta-9-tetrahydrocannabinol	Cannabinoid	MIXED May improve food intake, weight gain	Possible endorphin receptor activation, Inhibition of prostaglandin, IL-1	[85,106-110]
Melanocortin antagonists	Adrenocorticotropic hormone antagonist	UNTESTED; prevention of anorexia, loss of lean body mass or basal energy (animal only)	Neuropeptide Y alteration or melanocortin-4 receptor antagonism	[112,113]
Thalidomide	Immunomodulatory	Limits weight and lean body mass loss	Decreases TNF-α, pro-inflammatory cytokines, nuclear factor kappa B, cyclooxygenase 2, angiogenesis	[124-126]
Etanercept	Immunomodulatory	Limits fatigue; improves adjuvant therapy adherence	Decreases TNF effect	[127]
Eicosapentaenoic acid/omega-3-fatty acids	Lipid	MIXED; may improve weight, appetite, quality of life	Decreases pro-inflammatory cytokines, proteolysis inducing factor	[129,130,133,137,140-142,146-152]
Rikkun-shito	Herbal Japanese medicine	Improves median survival with gemcitabine (pancreatic cancer); improves anorexia, GI dysmotility, muscle wasting, anxiety	Unknown	[154,155]
Corticosteroids	Immunomodulatory	Improves appetite and quality of life	Various mechanisms	[156,157]
Formoterol	β2-adrenergic agonist	UNTESTED	Protein and muscle degradation antagonism	[170]
Erythropoetin	Glycoprotein hormone	Improves patient’s metabolic and exercise capacity	Decreases production of IL-6	[171-173]
ACE inhibitors	Heart medications	Reduce wasting of muscle mass	Inhibit TNF-α production	[174]
β-blockers	Heart medications	Preserved body weight, and lean and fat mass, and improved the quality of life	Normalized Akt phosphorylation	[175]

One proposed mechanism of cancer cachexia is that it is an integrated physiological response of substrate mobilization driven by inflammation[23].

There is an increase in pro-inflammatory cytokine activity during cancer progression[24,25], and systemic inflammation is a hallmark of cancer cachexia, indicated by the production of acute-phase response (APR) proteins such as C-reactive protein (CRP) and fibrinogen[26,27].

CRP is considered to be an accurate measure of the pro-inflammatory cytokine activity[28] that has been implicated in muscle wasting[29].

The APR is related to the inflammation and weight loss seen in cachexia[30,31] and the reduced quality of life and shortened survival of cachexia patients[10,32–35].

These phenomena increase muscle catabolism and transfer amino acids from muscle anabolism toward the amino acid pool required for APR protein anabolism[36,37].

It has been suggested that eicosanoids also mediate inflammation in cancer cachexia[38–40].

There is considerable evidence that signaling through cytokines and myostatin/activin pathways has a role in cancer cachexia and anorexia[41–43] (Figure ​(Figure1).1). Numerous cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and interferon-gamma (IFN-γ), have been postulated to play a role in the etiology of cancer cachexia[44–52]. T

he cytokines are transported across the blood-brain barrier where they interact with the luminal surface of brain endothelial cells causing release of substances that affect appetite[53].

Receptors of TNF-α and IL-1 are found in the hypothalamic areas of the brain, which regulates food intake. Anorexia induced by both TNF-α and IL-6 can be blocked by inhibitors of cyclooxygenase, suggesting that a prostaglandin, such as PGE2, may be the direct mediator of appetite suppression[54].

The role of TNF-α in mediating cancer cachexia is supported by evidence that intraperitoneal injection of a soluble recombinant human TNF-receptor antagonist improved food take and weight gain in tumor-bearing rats[55].

TNF-α increases gluconeogenesis, lipolysis and proteolysis, decreases the synthesis of proteins, lipids and glycogen, induces the formation of IL-1[17], and stimulates the expression of Uncoupling proteins (UCP) 2 and UCP3 in cachectic skeletal muscle[8].

Despite the fact that TNF-α induces the symptoms of cachexia, its inhibition has not been shown to stop or to reverse cancer cachexia[49].

This indicates that though TNF-α may be involved in the development of cachexia, it is not solely responsible for the effects seen in cachectic patients.

IL-1 concentrations increase in the cachectic state and have been known to cause similar effects to TNF-α[56].

IL-1 induces anorexia in cachectic patients as it causes an increase in plasma concentrations of tryptophan, which in turn increases serotonin levels, causing early satiety and suppressing hunger[57].

Increased tryptophan leading to associated increased serotonin production from the hypothalamus has been linked to anorexia[57,58].

A conflicting study showed that IL-1 did not affect food intake or weight loss, suggesting that IL-1 has a local effect on a particular tissue or the exogenous doses of IL-1 must be larger in order to see characteristics of cachectic state[59].

IL-6 is an important mediator in the defense mechanism of humans through its regulation of immune responses[60].

Concentration levels of IL-6 increase transferrin in cancer patients[28]. Levels of IL-6 were observed to be higher in patients with cachexia than weight-stable patients.

Although IL-6 may have an important role in the development of cachexia, it is not considered to be solely responsible, working through indirect action, indicated by the failure of IL-6 administration to reproduce cachexia in animal model[17].

As such, it is likely that a complex interplay of these factors is responsible for cachexia, rather than each working in isolation[61].

However, since there is limited variation in levels of circulating cytokines[62], and circulating cytokines are produced by isolated peripheral mononuclear cells, it is speculated that local production in affected tissues is more important and relevant to cachexia than systemic circulation of these factor[63].

Signal transducers and activators of transcription 3 (STAT3) is a member of the STAT family of proteins. STAT3 function as essential signal transducing effector proteins of cytokine-induced pathways that control the development, proliferation, differentiation, homeostasis of many cell types[64]. STAT3 activation is a common feature of muscle wasting. STAT3 is activated in muscle by IL-6 and by different types of cancer and sterile sepsis[65].

It is not certain whether the cytokine production is primarily from tumor or host inflammatory cells. It has been hypothesized that either tumor cell production of pro-inflammatory cytokines or the host inflammatory cell response to tumor cells is the source of the APR protein seen in many malignancies and in cachexia[66].

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In this study, the researchers showed that in order to trigger cachexia, the CD8 T cells required additional signals from the antiviral cytokine type I interferons, and needed to recognize the virus.

This study elucidates the inflammatory drivers of infection-associated cachexia and offers a valuable model for future investigations into the mechanisms of infection-associated cachexia.

This will allow for new molecular insights into how infectious pathogens including HIV, mycobacterium tuberculosis or parasites cause cachexia. Co-author Dr. Andreas Bergthaler says, “We are convinced that future studies that compare cachexia in the context of both infection and cancer, ideally through the integration of experimental models and clinical patient data, are going to provide much needed advancements for our understanding of this still very mysterious disease.”

Such new insights from basic research may lead to innovative therapeutic strategies for cachexia and associated life-threatening chronic diseases.

More information: CD8+ T cells induce cachexia during chronic viral infection, Nature Immunology (2019). DOI: 10.1038/s41590-019-0397-y , https://www.nature.com/articles/s41590-019-0397-y

Journal information: Nature Immunology
Provided by CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences