Malaria exposure decreases SARS-CoV-2 mortality

Another "conspiracy" becomes reality

As my readers know I abhor sending sequential e-mails, especially “content light” or what I call “algorithmic fluff”, but sometimes I indulge myself. I indeed laughed a lot this morning after opening up my tablet and seeing this paper hahaha.

For context.

SARS-CoV-2 antibodies can help cause Dengue ADE

In the article above I cover a very interesting paper, but that wasn’t the main reason I did it, the primary reason was that the findings in the paper were a “conspiracy theory” early in 2020, and I stated that many of our “conspiracy theories” became truth as years went by, and I did expect others to become truth... And here we are. Another “conspiracy theory” ends up being true.

Prior exposure to malaria decreases SARS-CoV-2 mediated mortality in K18-hACE2 mice without influencing viral load in the lungs

Prior context, very early in the pandemic, when countries were facing a massive deluge of severe respiratory sickness and pneumonia (and basically killing people by intubating them) an easy-to-spot trend surfaced, fast. Countries where malaria was endemic experienced lower mortality than “first-world countries”. This was one of the reasons that early on independent researchers went insane on Ivermectin FYI.

Before delving into this, I would like to point out the absurd level of intellectual honesty the authors present here, there is a degree of scientific rigor when modeling diseases using different methods that is often washed away on most papers (probably because scientists for the majority of time write for other scientists).

Here the authors used transgenic mice expressing human ACE2 receptors, which they stated multiple times the same I thought while reading the paper “There are caveats, mice often respond differently than humans, humans are more complex”. They wanted to see if exposing the mice to SARS-CoV-2 after 4 to 5 weeks after recovering from acute Plasmodium Chabaudi, a Plasmodium that causes malaria in rodents is pretty close to human malaria, influenced our response towards Covid infection. Measuring the viral loads, cytokines, and other inflammatory markers 6 days post-Covid infection.

Here is where things get rather interesting. There were no significant differences between the viral loads in Malaria-recovered+Covid-infected mice compared to the Covid-infected mice (controls), so the theoretical protection is not anti-viral itself. However, the cytokine profile (the groups of cytokines present in each group) was distinct in the Malria+SARS2 mice compared to controls. IL-9, IL-10, IL-12p40, Eotaxin, GMCSF, KC, and MCP-1 were significantly low in the Malaria+SARS2 mice.

It is worth noting that the significantly different cytokines have distinct functional profiles: GM-CSF, IL-9, KC (CXCL1), and MCP-1 in homeostasis, neutrophil recruitment, and chemotaxis; IL-10 and Eotaxin during anti-inflammatory response and IL12p40 suggestive of Th1 differentiation. Lower levels of all the above cytokines in the test group is suggestive of differences in hematopoiesis and cellular homeostasis and inflammatory responses in mice that had experienced malaria and subsequently infected with SARS-CoV-2.

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This suggests that SARS-CoV-2 mice previously infected with malaria have heightened overall host immune response in comparison to mice infected with only SARS-CoV-2.

Cytokines measurements

Such as Long Covid, severe Covid is multifaceted, it also has multiple sub-groups of “critical stages” you can observe the exact response described here, high levels of many of these, with lower levels of some. It is incredibly complex, but per the author’s findings, previous Malaria-infected mice have a very different immune response to the virus, and they experience a higher elevated response to many ISG (Interferon Stimulated Genes, something that fails both in Long Covid and severe cases).

They also tested for antibody cross-reactivity, something we are now aware with one of the common colds (it is a coronavirus) providing protection against SARS-CoV-2 infection and severity. No significant cross-reactivity was detected. The proposed mechanisms by the authors since there is a substantial difference between animal model of diseases and human infection.

1. significant hematological disturbances caused by malarial infections in K18 hACE2 mice in terms of increased anemia, granulopoieses etc.

2. induction of trained immunity by long protracted malarial infections - Plasmodia are known to induce such immunity or induction of tolerance that protects hosts against severe debilitating disease

3. significant changes in blood coagulation cascade that malaria are known to induce since adverse prognosis in COVID-19 is often attributed to blood coagulation in lungs

4. induction of auto-antibodies to carbohydrate moieties induced in malaria [20, 25] that have been proposed to play a role in COVID-19

While reading this paper my mind was already going into certain places, but when I reached the part of “induction of tolerance”… Among the many things I learned in the past 2 years, one that has stayed at the top of my head for the last 8 months has been “Endotoxin interacts with many other toxins”. And Toll-like receptors are responsible for initiating a looooooooot of our immune responses.

In this meta-analysis (analyzing a lot of papers and finding the trend between them), the authors found that each Toll-Like Receptor plays a role in regards to Malaria, TLR1, 9, and 4 are associated with parasitemia, TLR2, and 6 with severity. Aligned with our interests are TLR2 and 4. TLR is not only a person unique in their activity, or disease but also race, an important distinction to be made here.

TLR2 (research conducted in Ghana and Uganda) found that TLR2 protects against severe malaria. TLR4 has a dual effect, where it can increase disease severity and also protect, it can also affect parasitemia. Malaria also predisposes certain groups to invasive bacteria infections. But here is where things get really interesting.

For over 40 years, there has been consistent evidence of the cross-tolerance between Malaria GPI (one of its “toxins”) and LPS, Endotoxin itself. They share similar cell signaling pathways, they share similar activation pathways of cells, and a well-documented state for Malaria is its “tolerant” state, by which people don’t develop severe disease, more common after multiple exposures.

In the case of Malaria, it is also able to induce Toll-Like Receptor tolerance (Endotoxin Tolerance is just a technical name for TLR4 tolerance) to hinder the absurd deluge of inflammation the body would experience when there is too much of the parasite around. Arguably some researchers believe that this is how the vaccine protects from severe disease and mortality while not influencing transmission in regards to SARS-COV-2 and Western vaccines.

It would be really interesting to see this hypothesis tested if the reason Malaria protects against mortality is because it induces a transient state of immune tolerance. It would be also illuminating to find, since this does not affect viral loads in the lungs just mortality (basically the excess inflammation), if this effect has any influence on the adaptation and evolution of the virus. Africa has become a “hotbed” for mutations, especially among its immuno-compromised population.

As another conspiracy theory becomes true, I pray to God that the one I initiated (based on observation and scientific curiosity) is never confirmed. I even changed the name of my hypothesis because of it.

I usually end up with all my articles with a similar phrase, but today will be different.

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In the case, I spend the next few days writing my next article (I refuse to stop again to write something else because something cool popped up), I wish everyone a fantastic weekend.