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Malaria inhibits Covid

June 10, 2020 - 17:50 -- Pierre Lutgen

 

The role of immunoglobulines E

In January 2020 we published together with 3 medical doctors from Africa: “Jérôme, Munyangi, Pascal Gisenya, Patrick Ogwang …Immunoglobulins in the skin lead to long-lasting prophylaxis. Pharm Pharmacol Int Journal, PPIJ, 2020, Issue1”, a paper which, if widely spread, could have had a dramatic impact on the way the present Covid-19 crisis is handled.

One of the key findings of their work is that immunoglobulins are higher in malaria endemic areas.

The total IgE level in a population is strongly related to the malaria endemicity in that area with concentrations over 500 ng/ml, with many values over 2000 ng/ml. In the European population its concentration is  low at 10 to 300 ng/ml. For example, 10 ng/ml in Sweden, 647 in Thailand, 2134 in Liberia.

     H Perlmann, H Helmby, IgE elevation and anti-malarial antibodies in Plasmodium falciparum malaria. Clin Exp Immunol. 1994 Aug; 97(2): 284–292

     Perlmann P, ElGhazali G, Blomberg MT: IgE and tumor necrosis factor in malaria infection. Immunol Lett. 1999, 65: 29-33. 10.1016/S0165-2478(98)00120-5.

This higher IgE level in endemic areas protects against Plasmodium infections. It is likely that it also protects against viral infections.

The production of IgE specific to different viruses strongly suggest an important role for these antibodies. 40 years ago, it was found that naturally occurring viral respiratory infections increased serum IgE levels in both nonatopic as well as atopic individuals. They decreased after the symptoms. But infected and/or vaccinated children and adults continue a long-term production of IgE anti-Influenza virus antibodies long term. The long -term production, up to two years, of IgE anti-Influenza virus antibodies may contribute to protective immunity against Influenza.

      L Perelmutter, L Potvin, P Phipps. Immunoglobulin E Response During Viral Infections. J Allergy Clin Immunol. 1979 Aug;64(2):127-30.

     Tamar A Smith-Norowitz , Darrin Wong, Martin H Bluth. Long Term Persistence of IgE Anti-Influenza Virus Antibodies in Pediatric and Adult Serum Post Vaccination with Influenza Virus Vaccine. Int J Med Sci. 2011 Mar 18;8(3):239-44. doi: 10.7150/ijms.8.239.

     O L Frick. Effect of Respiratory and Other Virus Infections on IgE Immunoregulation. Review J Allergy Clin Immunol. 1986, 1013-8.

 

Artemisia and Covid: friend of foe?

If malaria protects against the corona virus this entails a crucial question: any reduction of malaria infections might lead to an increase in viral infections.

The conclusion we reached is that the Artemisia plants protect against both, malaria and virus, but artemisinin and derivatives only reduce malaria but may enhance viral infections. This hypothesis of course needs further research.

The prophylactic efficiency of Artemisia annua was first discovered and documented by Patrick Ogwang in several papers.

       Ogwang Patrick Engeu: Evaluation of Artemisia annua L for Malaria prophylaxis. Doctoral Thesis. Makerere University. 2012. Reg. Number 2008/HD 17/4952U

In a Chinese trial a significant boosting of IgGs was noticed by the administration of the aqueous extract of Artemisia rupestris.

       Zhang A, Wang D, Li J, Gao F, Fan X, the effect of aqueous extract of Artemisia rupestris L. (an influenza virus vaccine adjuvant) on enhancing immune responses and reducing antigen dose required for immunity. PLoS ONE 2017, 12(8): e0183720

IgE elevations are the expression of CD4+ cells and we have been able to demonstrate that these are increased by the administration of Artemisia annua and Artemisia afra. CD4+ cells are already induced in the pre-erythrocytic stages of malaria. This leads to a wide range of antibodies including some specific immunoglobulines.

      Constant Kansango Tchandema, Pierre Lutgen. In vivo trials on the therapeutic effects of encapsulated Artemisia annua and Artemisia afra. Global Journal for Research analysis 2016, 6, 228-234

      D Perez-Mazliah, J Langhorne. CD4 T-cell subsets in malaria revisited: Frontiers in Immunology, 2015,5, article 671

This is in line with information received from Patrick Ogwang, Mbarara University:  Artemisia annua drinking raises immunoglobulines.

However, monotherapy with artemisinin may have the opposite effect. In a study in China artesunate suppressed the humoral immune responses.

      P Y Lin, Z M Feng, J Q Pan, D Zhang, L Y Xiao. Effects of Artesunate on Immune Function in Mice. Zhongguo Yao Li Xue Bao. 1995 Sep;16(5):441-4.

Even worse, several papers report haemolytic anemia after treatment with artemisinin derivatives and particularly with IV artesunate

     K Rehman, F Lorsch, P Kresmner. Hemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis, 2014, vol 29 268-273

Serious side effects were also reported in France after IV artesunate treatment. Artesunate decreases hemoglobulin, platelets, erythrocytes and immunoglobulins

      Martin Danis, Marc Thellier, Le paludisme grave à P. falciparum en France, 2000-2011 : évolution épidémiologique et nécessité d’une nouvelle prise en charge thérapeutique. Bull Acad Nat Méd 3, 699-716, 2013

 

How do IgE protect against viral invasion?

The main entry port for viruses are mucosal tissues and skin.

The skin of most animals is an effective barrier against viral infections. However, viruses can pass through cuts or abrasions. Antibodies migrate and bind to wounded tissues. Antibodies could block invasion in several ways.

A recent paper highlights an important finding. After plasma infusion, IgE in the vascular circulation and serum had a half-life of 2 days but positive skin tests results were still demonstrated after 50 days. This long-life of the IgE in the skin may play an important role in prophylaxis.

        MG Lawrence, JA Woodfolk, Half-life of IgE in serum and skin. J Allergy Clin Immunology, 2017, 139, 422-428.

IgE also accumulate in keratotinocytes and epithelial cells and contribute to the barrier properties. Some people apply wormwood directly to the skin for alleviating insect bites.

       O Kortekangas-Savolainen, S Peltonen, K Pummi, IgE-binding Components of Cultured Human Keratinocytes in Atopic Eczema/Dermatitis. Allergy. 2004 Feb;59(2):168-173

       Sabine Altrichter, Ernst Kriehuber, Serum IgE Autoantibodies Target Keratinocytes in Patients with Atopic Dermatitis Journal of Investigative Dermatology (2008) 128, 2232–2239

Immunoglobulin E can be highly elevated in the airway mucosa and in saliva independently of IgE serum levels. IgE that is locally produced in the target organ could have diagnostic and therapeutic importance. These antibodies could block infections in several ways.

      E A Grönblad. Concentration of Immunoglobulins in Human Whole Saliva: Effect of Physiological Stimulation. Acta Odontol Scand1982;40(2):87-95

A few decades ago, the almost complete absence of infectious HIV in saliva was noticed. Inhibition of HIV may be partly due to several inhibitors of viruses that are present in the saliva. Incubation of HIV-1 with human saliva followed by addition of the mixture to susceptible cells leads to partial or complete suppression of viral replication in vitro.

       Malamud D, Abrams WR, Barber CA. Antiviral Activities in Human Saliva. Adv Dent Res. 2011 Apr; 23(1): 34–37.

        Fultz PN Components of saliva inactivate human immunodeficiency virus.  Lancet. 1986; 2:1215

It was found that age differences were much greater in salivary antibodies than in serum; older adults had reduced salivary secretion rates of IgA and IgE. This decline in local immunity may contribute to increased infection risk in the elderly, as it was seen in the Covid-19 pandemics.

        Abdollah JafarzadehI; Mostafa SadeghiII. Salivary IgA and IgE levels in healthy subjects: relation to age and gender. Braz. oral res. 2010, vol.24 no.1 

Comments

Submitted by Pierre Lutgen on

A recent paper from Odisha,India confirms our hypothesis that malaria may inhibit corona.
Comparing antibodies in healthy subjects in malaria-endemic areas (IgG: 144.62±47.23; IgM: 19.93±15.08) to residents of non-endemic regions (IgG: 30.15±9.3; IgM: 8.5±6.1) demonstate a possible cause-effect relationship. Further validation of this hypothesis might be established from other P. falciparum endemic areas of the world

Submitted by Anonymized User (not verified) on

Another paper confirms that the hypothesis proposed by Munyangi and Lutgen is fact more than speculation.
This year Italian people were living a severe crisis due to a Coronavirus disease (COVID-19). The North of Italy, is particularly affected with a great proportion of severe acute respiratory syndrome. Bergamo is the epicenter with up to 35% of the population infected.

In the northern Italian regions the presence of recently immigrated African people, usually employed in iron-steel factories and agricultural works, is high. Now, among the people in the hospitals with moderate or severe COVID-19, the presence of black people is very low. According to the data of Italian Superior Institute of Health, in Bergamo, the black people with moderate to severe COVID-19 are about 1,6% of COVID-19 patients
This huge difference could be due to a different genetic susceptibility of Africans. However it is known that in African-Americans the severity of COVID-19 is high.
In Subsaharan Africa malaria is one of the diseases which cause significant morbidity and mortality. We speculate that anti-malarial immunity may also play a protective role against corona. Individuals who have had malaria or asymptomatic malaria have antibodies (IgG) to Plasmodium specific antigens.
Aurora Parodi and Emanuele Cozzani⁎
Coronavirus disease 2019 (COVID 19) and Malaria.
Med Hypotheses. 2020 Jun 25

Submitted by Anonymized User (not verified) on

Artemisia plants are very rich in linoleic acid and potassium.
Both could have a detrimental effect during a viral infection.

Viruses exposed to high POTASSIUM display enhanced infectivity, thus identifying K+ as a newly defined trigger that helps promote viral infection
Many enveloped viruses enter cells through the endocytic network, from which they must subsequently escape through fusion of viral and endosomal membranes. This membrane fusion is mediated by virus-encoded spikes that respond to the dynamic endosomal environment, which triggers conformational changes in the spikes that initiate the fusion process.

Punch EK, Hover S, Blest HTW, Fuller J, Hewson R, Fontana J, Mankouri J, Barr JN. J Biol Chem. 2019 Feb 15;294(7):2579. doi: 10.1074/jbc.AAC119.007718. PMID: 30765512 Free PMC article. No abstract available.

LINOLEIC ACID intake is associated with increased mortality from COVID-19.

El-Kurdi B, Khatua B, Rood C, et al. Mortality From Coronavirus Disease 2019 Increases With Unsaturated Fat and May Be Reduced by Early Calcium and Albumin Supplementation. Gastroenterology. 2020;159(3):1015-1018.e4. doi:10.1053/j.gastro.2020.05.057

Some COVID-19 patients go on to develop severe infection with organ failure, potentially leading to death, and one of the contributing factors appears to be toxicity from the release of stored unsaturated fatty acids (PUFAs),
Separately, on analyzing global COVID-19 mortality data and comparing it with 12 risk factors for mortality, they found unsaturated fat intake to be associated with increased mortality. This was based on the dietary fat patterns of 61 countries in the United Nations' Food and Agricultural Organization database. Surprisingly, they found saturated fats to be protective. The pattern of disease is largely determined by a change in immune profile caused by metabolites of dietary linoleic acid.

This has been confirmed in another recent paper : A direct structural link between SARS-CoV-2 spike and linoleic acid, a key molecule in inflammation, immune modulation and membrane fluidity

Christine Toelzer, Kapil Gupta, Sathish K.N. Yadav,
doi: https://doi.org/10.1101/2020.06.18.158584

A. Sammon. Dietary linoleic acid, immune inhibition and disease, Postgrad Med J. 1999 Mar; 75(881): 129–132

Review of the evidence available in published literature supports a radical change in viewpoint with respect to Covid in countries where maize, rich in linoleic acid, is the predominant dietary component.

Submitted by Pierre Lutgen on

The comment « Do Artemisia annua infusions enhance Covid ? » indeed is intriguing.

A team of researchers at the Max Planck-Bristol Center for Minimal Biology and Bristol's School of Biochemistry studied the SARS-Cov-2 structure by a cryomicroscopy imaging technique. One of the most notable characteristics of the virus are its spike proteins, which allow the virus to bind to the different cells in the body, to find a cellular gateway to invade them.

Upon the analysis of the molecular structure of the spike protein, the team has found something interesting. They revealed the presence of a small molecule, called linoleic acid (LA), which was discovered in a customized pocket within the spike protein.

The implications of this discovery are puzzling. Linoleic acid appears to be the molecule which is at the center of those functions that go haywire in COVID-19 patients, with terrible consequences, basically disarming much of the body's defenses.

Toelzer, C., Gupta, K., Yadav, S., et al. Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein. Science 21 Sept 2020. ://science.sciencemag.org/content/early/2020/09

What was found by this Max Planck study for linoleic acid and Covid, does not necessarily apply to malaria. The situation could even be the reverse. Linoleic acid inhibits the growth of Plasmodium parasites.

Jérôme Munyangi, Pierre Lutgen, Artemisia plants, arachidonic and other polyunsaturated fatty acids. Malaria World Journal. 2020, 11:3

Krugliak M, Deharo E, Shalmiev G, Sauvain M, Moretti C, Ginsburg H. Antimalarial effects of C18 fatty acids on Plasmodium falciparum in culture and on Plasmodium vinckei petteri and Plasmodium yoelii nigeriensis in vivo. Exp Parasitol. 1995 Aug;81(1):97-105.

Singh S, Chitnis CE. Molecular Signaling Involved in Entry and Exit of Malaria Parasites from Host Erythrocytes. Cold Spring Harb Perspect Med. 2017;7(10):a026815. 105

Submitted by Pierre Lutgen on

Vitamin E and linoleic acid are antagonistic.

Dam H. Interrelations between vitamin E and polyunsaturated fatty acids. Bibliotheca Nutritio et Dieta. 1970 ;15:114-128.
Raederstorff D, Wyss A, Calder PC, Weber P, Eggersdorfer M. Vitamin E function and requirements in relation to PUFA. Br J Nutr. 2015;114(8):1113-1122.

Susceptibility to oxidative stress is a well-established feature of the malaria parasite. The antioxidant Vitamin E will inhibit this oxidative stress and favour the growth of Plasmodium. Nutritional manipulation by dietary means can have a profound effect on the growth of the parasite. In particular, rapid induction of vitamin E deficiency in mice by feeding highly unsaturated fatty acids (fish oil) strongly suppresses plasmodial growth.
O. A. Levander and A. L. Ager , Malarial parasites and antioxidant nutrients January, (Human nutrition and parasitic infection) , 1993, 107. pp. S95-S106

Vitamin E (α-tocopherol) is known to affect inflammatory responses in different tissues, including the lung. Vitamin E occupies a leading position among the antioxidants tested against influenza virus infections in mice. This is because of its efficacy in preventing oxidative damage through its free-radical scavenging activity. During influenza virus infection, a decrease in natural antioxidant vitamin E was documented. In the presence of antioxidant deficiency, when all cell membranes are exposed and/or damaged, influenza infection proceeds with severe pathology and results in serious damage at all levels in the body.

Milka Mileva and Angel S. Galabov (October 24th 2018). Vitamin E and Influenza Virus Infection, Vitamin E in Health and Disease, Jose Antonio Morales-Gonzalez, IntechOpen, 2018, DOI: 10.5772/intechopen.80954.

It appears that in elderly people higher concentrations of vitamin E are required to fight viral infections. The effects of supplementation with vitamin E were investigated on resistance to influenza infection in young and old animals. While vitamin E-supplemented young mice showed only a modest reduction in lung viral titre, vitamin E-supplemented old mice exhibited a highly significant reduction in viral lung titre.

Hayek MG, Taylor SF, Bender BS, Han SN, Meydani M, Smith DE, et al. Vitamin E supplementation decreases lung virus titers in mice infected with influenza. The Journal of Infectious Diseases. 1997;176:273-276
Mileva M, Bakalova R, Tancheva L, Galabov A, Ribarov S. Effect of vitamin E supplementation on lipid peroxidation in blood and lung of influenza virus infected mice. Comparative Immunology, Microbiology and Infectious Diseases. 2002;25:1-11
Sung Nim Han and Simin Nikbin Meydani. Vitamin E and infectious diseases in the aged, Proceedings of the Nutrition Society, 1999, Volume 58, Issue 3, pp. 697-705
Meydani SN, Barklund MP, Liu S, Meydani M, Miller RA, Cannon JG, et al. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. The American Journal of Clinical Nutrition. 1990;52:557-563
Artemisia plants are rich in linoleic acid, which is beneficial against malaria, but which might interfere with the positive role of Vitamin E in viral infections.

It is important that any nutritional supplement recommended against Covid, especially for elderly, be evaluated for its benefits ans drawbacks.