The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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Toxoplasma gondii Infection Is Associated with Mitochondrial Dysfunction in-Vitro

Discussion in 'Other Health News and Research' started by nanonug, Mar 7, 2018.

  1. nanonug

    nanonug Senior Member

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    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733060/

    Abstract
    Upon invasion of host cells, the ubiquitous pathogen Toxoplasma gondii manipulates several host processes, including re-organization of host organelles, to create a replicative niche. Host mitochondrial association to T. gondii parasitophorous vacuoles is rapid and has roles in modulating host immune responses. Here gene expression profiling of T. gondii infected cells reveals enrichment of genes involved in oxidative phosphorylation (OXPHOS) and mitochondrial dysfunction 6 h post-infection. We identified 11 hub genes (HIF-1α, CASP8, FN1, POU5F1, CD44, ISG15, HNRNPA1, MDM2, RPL35, VHL, and NUPR1) and 10 predicted upstream regulators, including 4 endogenous regulators RICTOR, KDM5A, RB1, and D-glucose. We characterized a number of mitochondrial parameters in T. gondii infected human foreskin fibroblast cells over a 36 h time-course. In addition to the usual rapid recruitment and apparent enlargement of mitochondria around the parasitophorous vacuole we observed fragmented host mitochondria in infected cells, not linked to cellular apoptosis, from 24 h post-infection. An increase in mitochondrial superoxide levels in T. gondii infected cells was observed that required active parasite invasion and peaked at 30 h post-infection. Measurement of OXPHOS proteins showed decreased expression of Complex IV in infected cells at 24 h post-infection, followed by decreased expression of Complexes I and II at 36 h post-infection. No change occurred in Complex V. No difference in host mitochondrial membrane potential between infected and mock-infected cells was observed at any time. Our results show perturbation of host mitochondrial function following T. gondii infection that likely impacts on pathogenesis of disease.

    PS. I am infected with this bugger.
     
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  2. Wonkmonk

    Wonkmonk Senior Member

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    How can one kill it?
     
  3. nanonug

    nanonug Senior Member

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    As of right now, there's no way to do it.
     
  4. aquariusgirl

    aquariusgirl Senior Member

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    how did you confirm? blood test? what led you to test?
     
  5. nanonug

    nanonug Senior Member

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    Yeap, blood test, IgG antibody. There was a point in time when I decided to test for everything that I could under the sun.
     
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  6. Runner5

    Runner5 Senior Member

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    Is this the disease carried by cats? The whole, "don't clean the litter box while pregnant because it has a bad effect on the fetus"?
     
  7. nanonug

    nanonug Senior Member

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    Yeap!
     
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  8. msf

    msf Senior Member

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    A lot of people have it. I found something that said that 11-40% of UK blood donors have it. So I think this is likely to be a secondary problem in people with ME.
     
  9. nanonug

    nanonug Senior Member

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    That's true, but not everyone has a mutation in the PRF1 gene that potentially results in hypofunction of the perforin protein, like I do. This mutation is present in roughly 3% of the population. At the very least, this leads to a cyst load much higher than that in people without perforin deficiencies.

    Interferon-gamma- and perforin-mediated immune responses for resistance against Toxoplasma gondii in the brain

    Abstract
    Toxoplasma gondii is an obligate intracellular protozoan parasite that causes various diseases, including lymphadenitis, congenital infection of fetuses and life-threatening toxoplasmic encephalitis in immunocompromised individuals. Interferon-gamma (IFN-γ)-mediated immune responses are essential for controlling tachyzoite proliferation during both acute acquired infection and reactivation of infection in the brain. Both CD4+ and CD8+ T cells produce this cytokine in response to infection, although the latter has more potent protective activity. IFN-γ can activate microglia, astrocytes and macrophages, and these activated cells control the proliferation of tachyzoites using different molecules, depending on cell type and host species. IFN-γ also has a crucial role in the recruitment of T cells into the brain after infection by inducing expression of the adhesion molecule VCAM-1 on cerebrovascular endothelial cells, and chemokines such as CXCL9, CXCL10 and CCL5. A recent study showed that CD8+ T cells are able to remove T. gondii cysts, which represent the stage of the parasite in chronic infection, from the brain through their perforin-mediated activity. Thus, the resistance to cerebral infection with T. gondii requires a coordinated network using both IFN-γ- and perforin-mediated immune responses. Elucidating how these two protective mechanisms function and collaborate in the brain against T. gondii will be crucial in developing a new method to prevent and eradicate this parasitic infection.
     
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  10. msf

    msf Senior Member

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    Perforin is part of the immune response to many pathogens, though, so you might have a problem with more than just toxoplasmosis.
     
  11. nanonug

    nanonug Senior Member

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    Perforin problems is exactly what Dr. Klimas found in patients with SEID.

    Chronic fatigue syndrome is associated with diminished intracellular perforin

    Abstract
    Chronic fatigue syndrome (CFS) is an illness characterized by unexplained and prolonged fatigue that is often accompanied by abnormalities of immune, endocrine and cognitive functions. Diminished natural killer cell cytotoxicity (NKCC) is a frequently reported finding. However, the molecular basis of this defect of in vitro cytotoxicy has not been described. Perforin is a protein found within intracellular granules of NK and cytotoxic T cells and is a key factor in the lytic processes mediated by these cells. Quantitative fluorescence flow cytometry was used to the intracellular perforin content in CFS subjects and healthy controls. A significant reduction in the NK cell associated perforin levels in samples from CFS patients, compared to healthy controls, was observed. There was also an indication of a reduced perforin level within the cytotoxic T cells of CFS subjects, providing the first evidence, to our knowledge, to suggest a T cell associated cytotoxic deficit in CFS. Because perforin is important in immune surveillance and homeostasis of the immune system, its deficiency may prove to be an important factor in the pathogenesis of CFS and its analysis may prove useful as a biomarker in the study of CFS.
     
  12. Wonkmonk

    Wonkmonk Senior Member

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    This is actually quite interesting because it might be a so far ignored, widespread co-infection in CFS, which might possibly cause problems.

    I read that even in the dormant state, latent Toxoplasmosis might be associated with psychological changes in the brain. This could be a greater (unrecognized) problem in CFS patients whose immune system might be ill-equipped to deal with many infection, possibly including T. Gondii. So T. Gondii might spread more easily in CFS and even in the latent state cause more neurological changes than in healthy people.

    Perhaps @Hip might also be interested in this.

    Wikipedia says that a combination of Clindamycin and Atovaquone can be used to treat a latent infection.

    https://en.wikipedia.org/wiki/Toxoplasmosis#Latent
     
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  13. Hip

    Hip Senior Member

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    I was looking into Toxoplasma gondii-induced ME/CFS recently (see this post). It seems a pretty rare cause of ME/CFS. I've almost never come across it on these forums.
     
  14. Wonkmonk

    Wonkmonk Senior Member

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    Thank you for the interesting information. So according to the article 4% of CFS cases might be triggered by Toxoplasma Gondii. That's a lot higher than I had thought.

    But I was thinking more in terms of latent Toxoplasmosis being a relevant co-infection (e.g. like Lyme in the Lerner protocol) that either causes additional or worsens existing neuro-psychologic symptoms (or symptoms related to mitochondria, see @nanonug's post). Or it might render treatment of the main CFS-sustaining pathogen more difficult or ineffective as Dr Lerner has found for a couple of bacterial co-infections.

    It may also be the case that the adverse effects Toxoplasma has on the brain (not too significant in most healthy people) are more pronounced in CFS patients.

    So I am wondering (for quite some time) if attempting to treat latent Toxoplasmosis would make sense in CFS patients.

    Will get tested next week. My mom is seropositive and I lived in a rural area for 2 decades. We had a cat and lots of other cats around our house, so chances are high I am also infected.
     
  15. Hip

    Hip Senior Member

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    The article in my post I linked to above says:
    So this article is saying that Toxoplasma gondii infection can sometimes lead to ME/CFS, but does not recommend any anti-toxoplasma drugs, except in cases where there is parasitaemia (= presence of Toxoplasma gondii parasites in the blood), and in these cases, anti-toxoplasma therapy is recommended. The presence of Toxoplasma gondii parasites can be detected by Toxoplasma gondii PCR testing.



    The seroprevalence of Toxoplasma gondii varies a lot from country to country. This study found the seroprevalence in Germany to be 20% in the 18–29 age group, and 77% in the 70–79 age group.
     
  16. Wonkmonk

    Wonkmonk Senior Member

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    Saw this. I am wondering if latent Toxoplasmosis, i.e. presence of bradyzoites in the brain and tissue without parasitaemia, might be an underestimated problem in ME/CFS just like herpesvirus/enterovirus infection without viraemia seems to be a problem.

    From what I know, many (most?) latent, persistent infections can be a trigger or problematic co-infection in ME/CFS. Then why not T. Gondii?

    So maybe eradication (or attempting eradication) might be warranted.
     
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  17. nanonug

    nanonug Senior Member

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    The amount of inflammation induced by latent toxoplasmosis is "proportional" to cyst load. Reducing cyst load may therefore be useful even if the parasite is not eradicated. The immune system's ability to fight initial infection depends a great deal on perforin activity. Pathogenic mutations in the PRF1 gene would therefore lead to higher cyst loads and consequently higher levels of chronic inflammation.
     
  18. Wonkmonk

    Wonkmonk Senior Member

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    A 3-week treatment with a combination of Clindamycin and Atovaquone significantly reduced the cyst burden in chronically infected mice. The effect was long-term and even improving over time.

    https://academic.oup.com/jac/article/50/6/981/809971
     
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  19. nanonug

    nanonug Senior Member

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    Yeap, I'm aware of that study. Clindamycin is easy to find. Atovaquone (by itself) not so much and I was unable to convince my infectious disease doctor to prescribe it (Mepron, in the US). I might try it if I put my hands on it although the complete lack of data regarding the use of this combo in humans for latent toxoplasmosis would force me to embark on quite a bit of trial and error. I'm not exactly risk-averse but it would be nice to have a bit more "guidance."
     
  20. Wonkmonk

    Wonkmonk Senior Member

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    @nanonug In Germany Atovaquone is only available as a combination with Proguanil as an antimalarial drug. I think that would work just as well, but one can never be sure. I didn't find any reports about interactions with Clindamycin, so I would suspect the combination is relatively safe, but one never knows.

    It's rather cheap in Germany, too.

    https://www.medizinfuchs.de/wirkstoff/atovaquon-534.html
     

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