Autophagy Deficiency in innate immune cells in a paradigm of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – AD-ME

Considering that susceptibility factors to Al-adjuvant intolerance constitute an important, though under-investigated field, our project aims to:
(i) Characterize in vitro the impact of the observed SNPs on autophagy flux and inflammatory responses to Al-adjuvants, using PBMCs from patients;
(ii) Use in vivo murine models of autophagy deficiency to assess if they are more sensitive to Al-adjuvant particles, in terms of biopersistency, systemic diffusion, inflammation and toxicity.

This work will provide a mechanistic understanding of how autophagy network controls the disposal and chronic toxic effects of Al adjuvant particles, build rationale for clinical interventions and respond to strong needs in vaccinology:
(i) Risk-based prevention by developing predictive genetic tests;
(ii) Personalized patient management using new treatments targeting autophagy;
(iii) Grounding development of safer vaccine adjuvants.

Our paradigm will offer promising novel insights into ME/CFS pathophysiology and treatment.

Our murine model will allow future investigations of a variety of autophagy-associated diseases suspected to be related to a variety of noxious environmental exposures (inhaled, prosthetic, ingested compounds), but in the frame of the present project we shall:
(i) Compare Al hydroxide (Alhydrogel®) to Al phosphate (AdjuPhos®), another widely used adjuvant;
(ii) Compare the effects of Al adjuvants alone to those of Al-containing vaccines;
(iii) Test preventive effects of pharmacologic autophagy activators.

The project was cited in the following papers:
Multipartner publications
1. Masson JD, Blanchet B, Periou B, Authier FJ, Mograbi B, Gherardi RK, Crépeaux G. 2020. Long term pharmacological perturbation of autophagy in mice: are HCQ injections a relevant choice? Biomedicines. 1;8(3). pii: E47. doi: 10.3390/biomedicines8030047.
2. To be published:
Autophagy snp in human diseases: the missing environmental link. Romeo, Grandjean et al. à soumettre.

Monopartner publications
3. Using Genetics To Dissect SARS-CoV-2 Infection. Brest P, Mograbi B, Hofman P, Milano G. Trends Genet. 2020 Nov 26:S0168-9525(20)30324-3. doi: 10.1016/j.tig.2020.11.007. Online ahead of print.PMID: 33309104.
4. Host Polymorphisms May Impact SARS-CoV-2 Infectivity. Brest P, Refae S, Mograbi B, Hofman P, Milano G. Trends Genet. 2020 Nov;36(11):813-815. doi: 10.1016/j.tig.2020.08.003. Epub 2020 Aug 10.PMID: 32828550.
5. A multifactorial score including autophagy for prognosis and care of COVID-19 patients. Domdom MA, Brest P, Grosjean I, Roméo B, Landi MT, Gal J, Klionsky DJ, Hofman P, Mograbi B. Autophagy. 2020 Dec;16(12):2276-2281. doi: 10.1080/15548627.2020.1844433. Epub 2020 Nov 29.PMID: 33249989.
6. Open questions for harnessing autophagy-modulating drugs in the SARS-CoV-2 war: hope or hype? Brest P, Benzaquen J, Klionsky DJ, Hofman P, Mograbi B. Autophagy. 2020 Dec;16(12):2267-2270. doi: 10.1080/15548627.2020.1779531. Epub 2020 Jun 19.PMID: 32521191

Scientific background: “Genes x environment” interplays are involved in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We shall focus on genetic autophagy deficiency and exposure to environmental particulate toxins. In the context of a growing vaccine policy (270 vaccines are currently under development), we shall focus on aluminum (Al) adjuvants of vaccines to explain why some people with ME/CFS seemingly intolerant to adjuvants have polymorphic autophagy genes, and how to detect them to limit the risk of adverse effects.
ME/CFS is a physical neurological disease affecting millions of people worldwide. It manifests by chronic fatigue, muscle pain, cognitive impairment and non-restorative sleep, and follows a prolonged course over years. ME/CFS pathophysiology remains unclear but a role for a variety of infections and environmental challenges has been proposed in cases of ME/CFS. Long-term persistency of intracellular pathogens or metals and mineral particles with immunostimulating effects has been detected in patients with ME/CFS, fuelling the idea that inappropriate clearance of pathogens or mineral compounds may cause “protracted immune stimulation that fails to switch off” eventually leading to immune related “burnout”. This fits well with recent evidence that ME/CFS patients are flush with cytokines until around the 3-year mark, at which point the immune system becomes exhausted and cytokine levels drop.
Some people carry genetic factors that confer susceptibility or resistance to particular environmental challenges. We explored if ME/CSF can be genetically “fingerprinted” and recognized to be at risk to develop the disease which may allow avoidance of specific exposures. We took advantage of getting biobanking of a large cohort of patients who developed ME/CFS after administration of Al adjuvant-containing vaccines, a condition also referred to as Autoimmune/inflammatory syndrome induced by adjuvants (ASIA).
ME/CFS patients followed by our team were historically identified by the detection in their deltoid muscle of an unusually longstanding histopathological lesion (up to >15 years) assessing intracellular Al-adjuvant persistency called macrophagic myofasciitis (MMF).
The contrast between the huge number of vaccinated people and the low rate of MMF detection suggests that some individuals have difficulty to clear out the adjuvant from their innate immune cells. We previously uncovered SNPs in autophagy genes in ME/CFS patients with MMF. Indeed, compared to healthy subjects from the 1000 genome project, 365 patients with MMF-ASIA displayed 7 SNPs involved in 6 autophagy genes with an apparent cumulative effect, more than 1 SNP being found in 93% of patients versus 14% of healthy subjects (patent underway). This strongly supports the view that adverse reactions to Al-based vaccines in adults respond to the “genes x environment interactions paradigm”.
Méthodology: Considering that susceptibility factors to Al-adjuvant intolerance constitute an important, though under-investigated field, our project aims to:
(i) Characterize in vitro the impact of the observed SNPs on autophagy flux and inflammatory responses to Al-adjuvants, using PBMCs from patients;
(ii) Use in vivo murine models of autophagy deficiency to assess if they are more sensitive to Al-adjuvant particles, in terms of biopersistency, systemic diffusion, inflammation and toxicity.
Results: This work will provide a mechanistic understanding of how autophagy network controls the disposal and chronic toxic effects of Al adjuvant particles, build rationale for clinical interventions and respond to strong needs in vaccinology:
(i) Risk-based prevention by developing predictive genetic tests;
(ii) Personalized patient management using new treatments targeting autophagy;
(iii) Grounding development of safer vaccine adjuvants.
Moreover, our paradigm will offer promising novel insights into ME/CFS pathophysiology and treatment.