Susceptibility to malaria: Genetic and environmental factors

Who is the most susceptible to malaria? What factors affect disease infection and progression? Read this to find out.
Last update29th Apr 2021

There are a number of factors that influence malarial infection and the course of the disease. Here we will discuss mechanisms that protect individuals from infection and factors that increase susceptibility to malaria.

Genetic traits that protect against malaria infection

Over the millennia, humans have evolved some protective mechanisms against malaria. Let’s first consider the genetic traits that offer some protection.

Some genetic traits cause shape changes in red blood cells (RBCs) which prevent the malaria parasite, Plasmodium, from invading the cell and initiating its reproduction. Typically, people carrying these traits do not show symptoms of disorders caused by the trait itself. There are three main genetic defenses that alter RBC shape:

  1. Sickle cell trait, the most common genetic defense, occurs in individuals with one abnormal allele of the ß-globin gene. It causes some RBCs to take on an abnormal sickle shape, reducing susceptibility to infection by P. falciparum.
  2. Hemoglobin AC affects the shape and structure of RBCs, protecting against P. falciparum infection.
  3. Hereditary ovalocytosis creates elliptically shaped RBCs which interferes with the parasite's ability to adhere to, invade, and grow within the cells.
Figure 1. Genetic traits that alter the shape of red blood cells (RBCs) include sickle cell trait, hemoglobin AC, and hereditary ovalocytosis. Shape changes interfere with the ability of Plasmodium to invade these RBCs and offer some protection against malaria infection.

Other genetic traits prevent the malaria parasite from growing within the cells. Let’s look at three examples:

  1. Glucose-6-phosphate dehydrogenase (G6PD) deficiency prevents the growth of P. falciparum within red blood cells.
  2. Beta thalassemia puts affected individuals at a lower risk of P. falciparum infection due to the persistence of hemoglobin F—fetal hemoglobin—which isn’t as easily broken down by the malarial parasite, making these cells somewhat resistant.
  3. Duffy antigens, receptors on RBCs, can be highjacked by P. vivax to help allow it to invade the cell. But many Africans are Duffy antigen-negative, which probably protects them against vivax malaria.
Figure 2. Genetic traits that prevent Plasmodium from growing inside cells include glucose-6-phosphate dehydrogenase (G6PD) deficiency, beta thalassemia, and absence of the Duffy antigen.

Acquired immunity against malaria infection

So those are the genetic factors, but what about acquired immunity?

It is not surprising to learn that if we are exposed to malaria, we will develop anti-malarial antibodies that confer some resistance against future infection. So, people who have been previously infected with malaria, and survived, especially those in endemic areas, will be less susceptible to future infection. But, those with acquired immunity who are re-infected will generally exhibit a lower disease severity.

Figure 3. Acquired immunity is possible in those individuals who have been previously exposed to malaria.

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Populations susceptible to malaria infection

Unfortunately, there are certain populations who are more susceptible to infection and have both higher morbidity and mortality rates than others.

The first group is pregnant women. The mortality rate for pregnant women infected with P. falciparum malaria is up to 50%. To make matters worse, the infection can cause massive hemolysis in the developing baby.

Figure 4. Pregnant women are more susceptible to malaria infection. The mortality rate for pregnant women infected with falciparum malaria is up to 50%.

Secondly, let’s consider babies under six months of age. Now, many African mothers have had several bouts of malaria and they have some antibodies, so their babies may well be protected after birth for three to six months by maternal antibodies. It's not complete protection, but it is some.

Figure 5. Babies between three and six months are temporarily protected by maternal antibodies, which include anti-malarial antibodies if their mother was exposed to malaria multiple times.

But because of their immature immune system, children between six months and five-years-old are quite susceptible to P. falciparum infection. In fact, they have morbidity and mortality rates at close to 10%.

Figure 6. Children between six months and five-years-old are more susceptible to malaria infection. The mortality rate for children in this age group is 10%.

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Recommended reading

  • Ashley, EA, Phyo, AP, and Woodrow, CJ. 2018. Malaria. Lancet391:1608­–1621. PMID: 29631781
  • Fairhurst, RM and Wellems, TE. 2014. “Malaria (Plasmodium Species)”. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Bennett, JE, Dolin, R, Blaser, MJ. 8th edition. Philadelphia: Elsevier Saunders. (Fairhurst and Wellems 2014, 3070–3090)
  • Phillips, MA, Burrows, JN, Manyando, C, et al. 2017. Malaria. Nat Rev Dis Primers3: 17050. PMID: 28770814
  • World Health Organization. 2019. World malaria report 2019. World Health Organizationhttps://www.who.int

About the author

John F. Fisher, MD MACP FIDSA
Professor of Medicine (Infectious Diseases) at the Medical College of Georgia, Augusta University, USA.
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