Malaria, tuberculosis, pneumonia and hemozoin

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Pascal Gisenya, Nsengiyumva Bati Daddy, Jérôme Munyangi, Mutaz Akkawi, Pierre Lutgen Already 30 years ago it was known that human monocytes which have ingested hemozoin are unable to neutralize pathogenic bacteria, fungi, and tumor cells, and that macrophage responses decline during the course of human and animal malaria. Hemozoin (Hz) is a biocrystal synthesized by Plasmodium and other blood-feeding parasites to avoid the toxicity of free heme derived from the digestion of hemoglobin during invasion of the erythrocytes. Schwarzer E, Turrini F, Ulliers D, Giribaldi G, Ginsburg H, Arese P. Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J Exp Med. 1992 Oct 1;176(4):1033-41 Amodu OK, Adeyemo AA, Olumese PE, Ketiku O, Gbadegesin RA. Intraleucocyte malaria pigment in asymptomatic and uncomplicated malaria. East Afr Med J. 1997 Nov;74(11):714-6. PMID: 9557443. Turrini F, Schwarzer E, Arese P. The involvement of hemozoin toxicity in depression of cellular immunity. Parasitol Today. 1993 Aug;9(8):297-300. doi: 10.1016/0169-4758(93)90129-4. PMID: 15463787. Hemozoin (malaria pigment) is found in many tissues during malaria infections. In mice that have self-cured from Plasmodium yoelii and Plasmodium chabaudi infections, liver hemozoin concentration and total content decreased for 6-9 months after parasite clearance. However, both spleen hemozoin concentration and total hemozoin content increased dramatically during this time period. Thus, hemozoin or hemozoin-laden macrophages continue to accumulate in murine spleens for at least several months after malaria parasitemia becomes undetectable. Levesque MA, Sullivan AD, Meshnick SR. Splenic and hepatic hemozoin in mice after malaria parasite clearance. J Parasitol. 1999 Jun ;85(3) :570-3. PMID: 10386458. This is well described in a recent paper. Plasmodium infection impairs host immunity to diverse bacteria, including S. pneumoniae, through multiple effects on innate immunity, and that a parasite-specific factor (Hz+bound bioactive molecules) directly contributes to Plasmodium-induced suppression of antibacterial innate immunity biomolecules. Due to the highly amphiphilic nature of hemozoin these biomolecules easily adsorb to hemozoin crystals. There remain important knowledge gaps that impede treatment of bacteria co-infections during malaria. Few studies have looked directly at the interactions between innate immune cells and Hz in the context of in vivo bacterial infection. Malaria and tuberculosis (TB) endemic regions overlap considerably, especially in sub-Saharan Africa. Although it is very likely that co-infections occur in these regions, not much is known about malaria-TB co-infections in humans, and how the interplay between these two infections might affect the prognosis of co-infected individuals. Hemozoin isolated from Plasmodium infected mice containing naturally associated bioactive molecules, such as host and parasite-derived proteins and lipids significantly impaired the ability of splenic phagocytes to control growth of intracellular bacteria. Following erythrocyte rupture, Hz is released into circulation and engulfed by phagocytic cells resulting in deposition in tissues and organs such as spleen, liver, brain, lungs, and bone marrow. In their study with Plasmodium yoelii infected mice, they found a decreased survival of infected mice following Salmonella pneumonia infection. Bacterial burdens trended higher in the lungs and were significantly higher in both the blood and spleen. These data demonstrate that Plasmodium infection also impairs control of bacteremia, and that the Plasmodium-driven susceptibility is prevalent beyond clearance of infected RBCs from peripheral circulation. This impaired antimicrobial functions of innate immune cells from African children with uncomplicated malaria was found to last up to 8 weeks after antimalarial treatment. Production of reactive oxygen species (ROS) is an important antibacterial effector mechanism used by phagocytic cells that is necessary for immunity to a multitude of bacterial pathogens. The results of this study clearly identify impairment of ROS production in neutrophils as a potential mechanism by which Plasmodium suppresses antibacterial innate immunity during systemic bacterial infections. An association between pulmonary pathology (SARS) and the levels of Hz deposition was also found. The impairment of ROS is not surprising, because during the parasite’s erythrocytic life cycle stages, it produces hemozoin to avoid oxidative stress Harding CL, Villarino NF, Valente E, Schwarzer E, Schmidt NW. Plasmodium Impairs Antibacterial Innate Immunity to Systemic Infections in Part Through Hemozoin-Bound Bioactive Molecules. Front Cell Infect Microbiol. 2020 Jun 30; 10:328. doi: 10.3389/fcimb.2020.00328. PMID: 32714882 A study in Portugal confirmed that repeated malarial episodes will lead to increased Hz deposition in host organs with potential detrimental effects. If Hz impairs cellular functions, such as phagocytosis and oxidative burst, the ability to kill intracellular bacteria might be impaired. It was also observed that hemozoin-containing macrophages participated in granuloma formation in response to tuberculosis infection. This might prove relevant in the context of a tuberculosis infection by the virulent strain M. tuberculosis, in which tighter control by immune cells is necessary to prevent tuberculosis dissemination. They found that during incubation of synthetic hemozoin (sHz) with whole blood monocytes and granulocytes readily absorb hemozoin PMBC cells loaded with hemozoin have a lower phagocytic capacity The Portuguese study also confirms the reduction of ROS production. The mechanism by which hemozoin ingestion leads to impairment of phagocytosis is not known. However, inhibition of ROS production by hemozoin ingestion seems to be associated to production of lipid peroxidation derivatives, which promote oxidation and damage of essential components of the oxidative response. They were also impressed by the long residence time of hemozoin in the body. Considering that the average life span of a mouse is around 850 days, it is impressive that hemozoin could still be detected in mouse organs 280 and 140 days. This represents approximately a quarter of the life span of a mouse. Assuming that the same happens in humans and considering that in malaria endemic regions, such as sub-Saharan Africa, the same individual is likely to get infected several times throughout life, then it is likely that the amount of hemozoin accumulated in organs is enormous. If intracellular hemozoin in these organs consistently contributes to impairment of functions of these cells, then affected individuals will potentially have a proportion of immune cells that respond to other pathogens at suboptimal levels. Frita, Rosangela, Malaria and tuberculosis co-infection: role for hemozoin immunosuppression. Teses de Doutoramento. Universidade de Lisboa, Faculdade de Medicina 2014, http://hdl.handle.net/10451/11435 The causal relationship between hemozoin and lung inflammation was investigated and confirmed by injecting P. falciparum-derived hemozoin intravenously into malaria-free mice. Deroost K, Tyberghein A, Lays N, Noppen. Hemozoin induces lung inflammation and correlates with malaria-associated acute respiratory distress syndrome. Am J Respir Cell Mol Biol. 2013 May;48(5):589-600. doi: 10.1165/rcmb.2012-0450OC The extensive work done by the University of Al-Quds in Palestine on beta-hematin inhibition by Artemisia and other plants may open a large array of possibilities to reduce the hemozoin load in the human body. Akkawi M, Jaber S, Abu-Remeleh Q, Engeu OP, Lutgen P (2014) Investigations of Artemisia Annua and Artemisia Sieberi Water Extracts Inhibitory Effects on Β-Hematin Formation. Med Aromat Plants 3 : 150. doi : 10.4172/2167- 0412.1000150

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