Sickle Cell genetic resistance to Malaria

Disease resistance is the ability to prevent or reduce the presence of

disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...

s in otherwise susceptible hosts. It can arise from genetic or environmental factors, such as incomplete

penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...

. Disease tolerance is different as it is the ability of a host to limit the impact of disease on host health. In crops this includes

plant disease resistance Plant disease resistance protects plants from pathogens in two ways: by pre-formed structures and chemicals, and by infection-induced responses of the immune system. Relative to a susceptible plant, disease resistance is the reduction of pathogen ...

and can follow a

gene-for-gene relationship The gene-for-gene relationship is a concept in plant pathology that plants and their diseases each have single genes that interact with each other during an infection. It was proposed by Harold Henry Flor who was working with rust (''Melampsora l ...

Genetic Factors

Incomplete Penetrance

An example of a genetic factor causing disease resistance is incomplete penetrance. Incomplete penetrance is the result of a genetic mutation not fully manifesting as the associated trait or disease. In the combined case of sickle cell anemia and malaria, individuals with one normal allele and one sickle cell allele, (heterozygous HbAS), are largely healthy due to incomplete penetrance. They do not experience the effects of having sickle cell anemia, (due to the incomplete nature of the mutation), and gain resistance to malaria. This is due to the altered shape of their red blood cells due to the partial sickle cell trait, which impedes the ''Plasmodium'' parasite, giving the individual resistance to the associated infection and disease caused by the parasite.

Specific Genes

Certain genes themselves provide disease resistance by directly enhancing the immune response or directly inhibiting pathogens. For example, the Mx1 gene directly encodes a protein that blocks the replication of some viruses, such as influenza, providing natural resistance in certain organisms (like mice). Similarly, Toll-like receptors (TLRs), which are naturally occurring proteins, are critical in recognizing pathogen-associated molecules, (including microbial and viral threats), and triggering immune responses. Notably, variations or specific alleles in these genes can strengthen the body’s ability to combat infections, showing how genetic traits can further contribute to innate immunity and pathogen resistance.

Hemoglobinopathies

Hemoglobinopathies are a class of monogenic disorders that impact the major red blood cell protein hemoglobin. Hemoglobinopathies interfere either with hemoglobin production or change hemoglobin’s protein structure, respectively splitting them into the two categories of thalassemias and structural variants. These disorders exist due to alpha- or beta-globin gene mutations, causing symptoms of moderate to severe anemia, organ damage, and reliance on blood transfusion for survival. Hemoglobinopathies provide an uncommon resistance against malarial infection, allowing an increased fitness of these mutations in regions where the mortality risk of malaria is high.

Hormonal Immunity

Sex hormones, otherwise known as gonadal steroid hormones, play a role in regulating immune system functions through their modulation of disease resistance and immune responses. Levels of type-1 interferon (IFN-I) cytokines involved in the stimulation of immune response and tumor necrosis factors (TNF) proteins involved in an inflammatory immune response can be altered by the introduction of testosterone hormones by individuals undergoing masculinizing gender-affirming treatment.{{Cite journal , last=Lakshmikanth , first=Tadepally , last2=Consiglio , first2=Camila , last3=Sardh , first3=Fabian , last4=Forlin , first4=Rikard , last5=Wang , first5=Jun , last6=Tan , first6=Ziyang , last7=Barcenilla , first7=Hugo , last8=Rodriguez , first8=Lucie , last9=Sugrue , first9=Jamie , last10=Noori , first10=Peri , last11=Ivanchenko , first11=Margarita , last12=Piñero Páez , first12=Laura , last13=Gonzalez , first13=Laura , last14=Habimana Mugabo , first14=Constantin , last15=Johnsson , first15=Anette , date=September 26, 2024 , title=Author Correction: Immune system adaptation during gender-affirming testosterone treatment , url=https://www.nature.com/articles/s41586-024-08081-w , journal=

Nature Nature is an inherent character or constitution, particularly of the Ecosphere (planetary), ecosphere or the universe as a whole. In this general sense nature refers to the Scientific law, laws, elements and phenomenon, phenomena of the physic ...

, language=en , volume=634 , issue=8033 , pages=E5–E5 , doi=10.1038/s41586-024-08081-w , issn=1476-4687 , pmc=11464365 , pmid=39317781 Interferons are synthesized by plasmacytoid dendritic cells (pDCs) which have toll-like receptors (TLR-7) that modulate their activity, so with the introduction of testosterone downregulating TLR-7 production in pDCs, interferons are consequently downregulated. Testosterone reduces the impact of IFN-I responses in pDCs while increasing the intensity of pro-inflammatory pathways involving TNF.

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