Tag: pathogenesis

Part 2 of 2: Inflammation and Exercise: friend or foe?

As I mentioned in Part 1 of this two-part post, inflammation is a two-edged sword, requiring a fine balance between initiation and termination, in order to promote health and not disease.

With this idea in mind, I came across a recent review article by Gleeson et al. in Nature Reviews Immunology, which focuses on the anti-inflammatory effects of exercise and its implications in health and disease.1

The authors observed that pathogenesis of various conditions associated with many metabolic and other diseases (such as diabetes, cardiovascular disease, certain cancers, dementia and so forth) have been shown to be dependent on the interplay of metabolic and immune processes, and appear to be associated with inflammation. Exercise, or high physical activity, is known to protect against the development of many of these conditions, and therefore, may have anti-inflammatory properties. The authors reviewed the existing literature to seek the evidence for that hypothesis.

The authors compiled a list of several possible mechanisms by which exercise exerts its anti-inflammatory effect. This includes:

  1. A reduction in visceral fat mass – this exerts an indirect effect to decrease inflammation, since accumulation of fat in the omentum, liver and muscles, as well as the expansion of adipose tissue, results in enhanced production of certain inflammatory mediators (such as TNF, Leptin, IL6, CCL2/MCP1, CCL5/RANTES etc.) and consequent reduction of anti-inflammatory cytokines (such as Adiponectin). An obese body lives in a persistent state of low-grade systemic inflammation, and therefore, fat-loss through exercise has an anti-inflammatory effect.
  2. Release of IL6 from working muscles – A fall in muscle glycogen content with exercise signals the muscles to secrete IL6, keeping the concentration of this pro-inflammatory cytokine high for the duration of the exercise. This rise in circulating IL6 appears to start off a cascade in which certain anti-inflammatory cytokines (IL10, IL-1RA) are elevated and exert their direct and indirect effects to minimize inflammation induced tissue damage. However, elevation of IL6 is dependent upon the duration of activity, and a significant increase requires 2 and a half hour of more of strenuous exercise.
  3. Increased levels of circulating cortisol and adrenaline – IL6 stimulates the release of the stress hormone, cortisol, from adrenal glands. Besides, exercise itself activates the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, thereby signaling the production of more cortisol and adrenaline from the adrenal gland, as well as adrenaline/noradrenaline from the adrenal medulla, for the duration of the exercise. Cortisol and the catecholamines (adrenaline and noradrenaline) are both known to have potent anti-inflammatory effects.

The authors also discussed a few other possibilities that don’t have enough evidence yet – such as exercise may (a) reduce the influx of macrophages (histiocytic inflammation) into adipose tissue, (b) prevent the adhesion of inflammatory cell to the inner wall (endothelium) of blood vessels, by reducing the expression of a surface molecule called ICAM-1, © attenuate the number of pro-inflammatory mononuclear leukocytes (monocytes) in the total blood pool; and so forth.

What first caught my attention was the authors’ surmise that exercise could reduce (downregulate) the surface expression of a set of receptor molecules (the TLRs) that are very important in the detection of and host response to microbial pathogens. Blood monocytes from physically active individuals had decreased TLR4 expression, and following an acute, prolonged bout of strenuous exercise, the expression of TLR1, TLR2 and TLR4 on monocytes was decreased for at least several hours. The reduction in TLR expression has been associated with decreased inflammatory cytokine production.
But this doesn’t augur well, since TLR1, TLR2 and TLR4 represent major mechanisms by which immune cells detect bacterial and fungal pathogens. Indeed, towards the end of the review, the authors comment on the repeated observation that “the long hours of hard training that elite athletes undertake appear to make them more susceptible to upper respiratory tract infections”. In addition, the anti-inflammatory cytokine IL10, produced copiously during extensive exercise, limits the effectiveness of pathogen-specific innate and adaptive immune responses.

Therefore, at the conclusion of the article, I was left unsure as to the benefits of exercise as propounded by the authors, especially from an anti-inflammatory mechanistic viewpoint. However, it must be said that much of the above-mentioned evidence of the anti-inflammatory (and thereby, beneficial) effect of exercise is circumstantial, judging by the indirect nature of many of the effects, as well as the dependence of the said effects on intensity and duration of the exercise. Neither the interplay between pro- and anti-inflammatory cytokines, nor their relative dynamics, appear to be well-understood in the context of exercise.

For example, in this review, the authors have not touched upon the conflicting evidence that during exercise, contracting muscles give rise to localized inflammatory responses through synthesis of pro-inflammatory cytokines IL1β, TNF and IL6, whose levels are not transitory but remain high for days. There is also evidence that the pro-inflammatory cytokines may mediate muscle growth, as well as muscle repair following injury; in fact, IL6 has been identified as an essential regulator of hypertropic muscle growth2 via satellite cells (muscle stem cells) which are also involved in skeletal and cardiac muscle repair.3 Therefore, suppression of IL6 in the long term (as hypothesized in the anti-inflammatory model) cannot be beneficial to the host as a whole. The hypothesis of omental and muscle fat leading to a beneficial reduction of Adiponectin1 is also suspect, since the absence of Adiponectin expression causes contractile dysfunction and phenotypical changes in skeletal muscle.4 There also appears to be a strong relationship between exhaustive exercise, such as marathon running, and chronic low-grade inflammation induced by the massive systemic release of several pro-inflammatory cytokines and chemokines, such as IL6, IL8, G-CSF, M-CSF and MCP1 (which mediate recruitment and activation of inflammatory effector cells, neutrophils and monocytes), although host tissue damage may be restricted by compensatory mechanisms.5

In conclusion, benefits of regular exercise and physical activity are well observed. But perhaps it is best not to draw, yet, all-encompassing mechanistic conclusions involving inflammatory processes, because inflammation is a highly complex process fine-regulated by many factors; it may indeed not be possible to consider all those factors properly in context. Different types and intensities of physical exercise may well stimulate or suppress certain inflammatory processes, but their exact nature and consequences seem far from understood.


1. Gleeson, M., Bishop, N., Stensel, D., Lindley, M., Mastana, S., & Nimmo, M. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease Nature Reviews Immunology, 11 (9), 607-615 DOI: 10.1038/nri3041

2. Serrano AL, Baeza-Raja B, Perdiguero E, Jardí M, & Muñoz-Cánoves P (2008). Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell metabolism, 7 (1), 33-44 PMID: 18177723

3. Grounds MD, White JD, Rosenthal N, & Bogoyevitch MA (2002). The role of stem cells in skeletal and cardiac muscle repair. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 50 (5), 589-610 PMID: 11967271

4. Krause MP, Liu Y, Vu V, Chan L, Xu A, Riddell MC, Sweeney G, & Hawke TJ (2008). Adiponectin is expressed by skeletal muscle fibers and influences muscle phenotype and function. American journal of physiology. Cell physiology, 295 (1) PMID: 18463233

5. Suzuki K, Nakaji S, Yamada M, Liu Q, Kurakake S, Okamura N, Kumae T, Umeda T, & Sugawara K (2003). Impact of a competitive marathon race on systemic cytokine and neutrophil responses. Medicine and science in sports and exercise, 35 (2), 348-55 PMID: 12569227

Part 1 of 2: Inflammation: A two edged sword

Inflammatory mechanisms are very important for the innate defence system of the body. When the host body encounters stimuli it perceives as harmful, such as pathogens and/or products thereof, injured cells or tissue, or any foreign object that irritates the surrounding tissue, the host often responds with a complex generalized response. A part of this response involves vascular tissues, leading to increased translocation of circulating white blood cells (WBC or leukocytes), especially the granule-containing cells (such as neutrophils) and mononuclear cells (such as monocytes), as well as plasma (containing necessary proteins, such as fibrin, complements, and immunoglobulins, a.k.a. antibodies), from blood to the area of injury. This process is known as inflammation.

There are many players in this, including immune defense cells already resident in the tissue; they secrete certain biochemical mediators (e.g. ‘cytokines’, ‘chemokines’, ‘prostaglandins’ and so forth), that initiate various biochemical events and act as beacons for the migrating leukocytes to home in on. The first batch of leukocytes would themselves secrete more of such mediators, in order to call in reinforcements. This is how the inflammatory response matures, involving the local vascular system, the immune system, and various cells at the site of injury.

What do these inflammatory immune cells do? These cells, now called ‘Effectors’, are able to kill the offending pathogens, destroy the remnants of injured cells or tissue, break down or bury the foreign object, so that the healing process can begin. Several non-cellular processes, associated with the plasma proteins, help inititate and propagate this inflammatory process, also taking part in healing.

Inflammation can be classified temporally as (a) acute – a short term process that often initiates within minutes or hours following injury and subsides upon resolution of the injury, or (b) chronic – a prolonged process in which inflammatory cells may progressively shift to the site of injury even after the deleterious stimulus is gone, causing persistent destruction of tissue.

Superficial acute inflammation, such as on the skin, may be observed as a zone of redness, hot to touch, prone to swelling, and often, tender. This is what happens after, say, an insect bite, frostbite, skin contact with plants such as Poison Ivy, or immune reactions due to hypersensitivity to certain medicines (e.g. metronidazole, an antibiotic, causes me to break out in hives; some allergic responses can cause inflammation of the airways, leading to respiratory distress). However, inflammation can equally occur in internal organs, and may cause a pain sensation when it reaches those areas that contain nociceptors (pain-sensitive nerve endings). This is how various non-steroidal anti-inflammatory drugs work; they reduce pain by inhibiting various molecules that are responsible for inflammation.

Chronic inflammation, on the other hand, is considered responsible for a large variety of unrelated human diseases, ranging from immune system disorders that cause unmitigated, exuberant inflammation – such as observed in allergic reactions; inflammatory injury to muscles (myopathies) or to various organ systems (e.g. inflammatory bowel diseases, pelvic inflammatory disease, and glomerulonephritis); various autoimmune disorders, and so forth; to non-immune diseases, such as certain cancers, atherosclerosis and ischemic heart disease.

As a student of host-pathogen interaction, I encounter inflammation from that specific context, but the principle remains generalizable. This concept has been nicely laid out in the Damage Response Framework of Microbial Pathogenesis proposed by Casadevall and Pirofski in 2003.1 One of the mechanisms by which microbe-induced damage is caused to the host tissue is inflammation, i.e. immune-mediated damage. Virulence (i.e. the ability to cause disease) of various bacterial, fungal and parasitic pathogens is often paralleled by their ability to incite various profiles of inflammation. For example (all from Ref. 1),

  • The etiological agent of tuberculosis, Mycobacterium tuberculosis, is a pathogen that causes disease in two ways: in immunocompromised individuals (such as HIV+ people), the host doesn’t mount an adequate response. Interestingly, in immune-sufficient individuals, the damage is mediated by a robust inflammatory response that the host generates against the bug.
  • A mutant of everyone’s beloved yeast, Saccharomyces cerevisiae, that has altered surface properties capable of eliciting a strong inflammatory response, is virulent in mice.
  • Lung damage in AIDS patients from pneuomonia induced by Pneumocystis carinii is mediated largely by the residual immune system, which is likely why corticosteroid-induced specific suppression of inflammation leads to better outcomes in patients.
  • The mold pathogen, Aspergillus fumigatus, causes disease in individuals with weak or strong immunity, and in the latter, the disease takes the form of exuberant inflammatory response and hypersensitivity reactions to Aspergillus antigens.
  • Neurocysticercosis, a debilitating neurological disorder, occurs when the host mounts a strong inflammatory response to the worm parasite Taenia solium, even if the worm is dead.

Therefore, evidently, inflammation is a two-edged sword, requiring a fine balance between initiation and termination, in order to promote health and not disease.

Click here to continue to Part 2.


1. Casadevall, A., & Pirofski, L. (2003). The damage-response framework of microbial pathogenesis Nature Reviews Microbiology, 1 (1), 17-24 DOI: 10.1038/nrmicro732

Additional Reading: The Wikipedia article on Inflammation is quite extensive and well-referenced.

Alcohol pwns inflammation; Or, saga of alcohol dehydrogenase from Aspergillus

Aspergillus fumigatus and various other Aspergilli are ubiquitous molds. These are hardy aerobic saprotrophs, growing as easily on breads and potatoes as on plants and trees. However, many Aspergilli are capable of growing in nutrient-deficient or nutrient-absent environments, and surviving in extreme conditions, such as high temperature (up to 55oC) and pH; for example, A. niger, the Black Mold, can grow happily on damp walls. I have observed A. fumigatus grow on the surface of a highly alkaline buffer (pH9; one of the pH meter standards).

In addition, A. fumigatus has been found to be highly tolerant of a wide range of oxygen levels, from atmospheric (21%) to moderately aerobic (~14% as in the lung alveoli), low (2-4% as in tissues), or hypoxic (<1.5% as found in compost piles), even to as low as 0.1% (Source: References available with the article under review). For an obligate aerobe, A. fumigatus has evolved remarkably robust mechanisms that allow it to tolerate and thrive in extremely hypoxic conditions. Needless to say that such mechanisms are likely to come mighty handy when causing disease.

Many of the Aspergillus species are known to cause disease in human and animals; of these, A. fumigatus is the most common causal agent of invasive pulmonary aspergillosis, a frequent and life-threatening complication in several immunosuppressed patient populations. Microscopic airborne spores (‘conidia’) of the mold, produced copiously, are inhaled by the host (human and animals). Immunocompetent hosts mount an innate immune response that eliminates the conidia; however, both immunocompromised hosts (such as cancer and transplant patients), who cannot mount an efficient enough response, and patients of other chronic lung/airway diseases (such as allergic asthma), who mount an excessive and unmitigated inflammatory immune response, are both vulnerable to the disease produced by A. fumigatus conidia.

In order to cause disease, the conidia primarily colonize airways or the lungs and, if successful in breaching the innate immune defence, germinates into hyphae, long finger-like projections, that invade the tissues and blood vessels. The mechanisms by which A. fumigatus is able to survive and grow in the host environment are not all well-understood. Based on previous studies which demonstrated that inability of certain mutants of A. fumigatus and the yeast pathogen, Cryptococcus neoformans, to grow under hypoxic conditions correlated with their reduced virulence in mouse models, Grahl et al., leading a multi-institutional group of investigators, set out to discover if A. fumigatus encountered such hypoxic conditions in the host lung and how it dealt with it while infecting the host.

They found that
(a) hypoxic microenvironments do occur in three distinct immunosuppressed murine models; they discovered this by using a chemical hypoxia detection agent, pimonidazole hydrochloride, that enabled cool, visual estimation of hypoxia in tissue via immuno-fluorescence (Figure 2). From the observed extent of hypoxia, fungal growth, and host immune responses in different immunosuppressive models, the authors inferred that “the host inflammatory response plays an important, but not exclusive, role in the generation of the hypoxic microenvironment.”
(b) alcohol is involved (perhaps not surprisingly, since hypoxia must be a stressful situation!).

No, really. Using a 400 MHz 1H-NMR, Grahl et al. could detect substantial ethanol in 4 out of 10 immunosuppressed mice infected with A. fumigatus at day 3 post-infection, but none in uninfected mice.

Figure S1 Grahl et al., 2011, PLoS Pathog 7(7): e1002145

In order to ensure that the ethanol in the lung was of fungal origin (and not a result of, say, some wild Bacchanalian orgy the mice partook of in the middle of the night), the authors tested and established that A. fumigatus was indeed capable of fermenting glucose to ethanol in vitro in media containing minimal (1%) glucose under hypoxic conditions (1% oxygen, Figure 1) after 48, 72, and 96 hours of growth.

Analyzing fungal genes involved in the alcohol fermentation pathway, the authors zeroed in on the A. fumigatus gene alcC encoding an alcohol dehydrogenase whose expression is enhanced significantly in response to hypoxia. Interestingly, this gene appeared not to be contributing to A. fumigatus‘s ability to grow under hypoxic conditions, nor to the virulence of the mold – since mutants lacking this gene was as virulent as the wild type A. fumigatus in all models of immunosuppressed mice. However, in the model with cyclophosphamide induced neutropenia, as well as the one with corticosteroid induced immunosuppression, the mutant mold strain producing no alcohol had greatly reduced growth with evidence of significant inflammation when compared to the wild type (Figure 8); in the mice infected with the mutant mold strain, increased recruitment of immune effector cells, particularly neutrophils (Figure 9), and associated altered cytokine responses (Figure 10) were observed in the lung.

In other words, the alcohol of fungal origin may modulate the immune response by suppressing the inflammation, which may offer a survival advantage to the mold in the tissue. As always, alcohol makes everything better, especially when the mold brews it by itself.

The authors discuss one important caveat of the study: the observation of ethanol production in only 4 of the 10 infected mice. They offer several possible reasons that may have contributed to this, such as the lack of a more sensitive method of detection, unsuitability of bronchoalveolar lavage fluid as the site of interest and so forth. It’d be of interest to see if better detection methods – which they say they are developing – improve upon these results.

Another important caveat that the authors didn’t discuss lies in the model, particularly the method of immunosuppression. Corticosteroid treatment impairs the antifungal action of immune effector cells; in mice treated with a single dose of the corticosteroid Triamcinolone, it is perhaps not surprising that at day 3 post infection there was a rebound increase in inflammatory cells, led by neutrophils, which are after all the principal effectors against Aspergillus. Unfortunately, the authors didn’t check cellular infiltrate status in mice immunosuppressed with cyclophosphamide which they gave at day -2 and day 3 of infection. Cyclophosphamide causes profound neutropenia – as the authors have noted – and at the given dose, the neutropenia usually lasts for 96 hours. So, by day 3, one would expect a rebound neutrophilia in these mice prior, of course, to the second dose. It would have been interesting to see the cellular composition of the infiltrates in the cyclophosphamide-treated mice. One would expect the inflammation in this case to be largely macrophage/monocyte in nature, perhaps.

Overall, a rather interesting study with some intriguing findings; a good read.

Pathogens&rft_id=info%3Adoi%2F10.1371%2Fjournal.ppat.1002145&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=In+vivo+Hypoxia+and+a+Fungal+Alcohol+Dehydrogenase+Influence+the+Pathogenesis+of+Invasive+Pulmonary+Aspergillosis&rft.issn=1553-7374&rft.date=2011&rft.volume=7&rft.issue=7&rft.spage=0&rft.epage=&rft.artnum=http%3A%2F%2Fdx.plos.org%2F10.1371%2Fjournal.ppat.1002145&rft.au=Grahl%2C+N.&rft.au=Puttikamonkul%2C+S.&rft.au=Macdonald%2C+J.&rft.au=Gamcsik%2C+M.&rft.au=Ngo%2C+L.&rft.au=Hohl%2C+T.&rft.au=Cramer%2C+R.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CResearch+%2F+Scholarship">Grahl, N., Puttikamonkul, S., Macdonald, J., Gamcsik, M., Ngo, L., Hohl, T., & Cramer, R. (2011). In vivo Hypoxia and a Fungal Alcohol Dehydrogenase Influence the Pathogenesis of Invasive Pulmonary Aspergillosis PLoS Pathogens, 7 (7) DOI: 10.1371/journal.ppat.1002145