**1. Introduction**

According to the world health organization, malarial cases are expected to double in recent times due to the much global focus to fight the covid-19 pandemic [1]. The global fight against the covid-19 pandemic slows down efforts to control or eliminate malaria as one of the life-threatening diseases worldwide. In 2018, 228 million cases of malaria were reported with 405 000 people died, and in Sub-Saharan Africa, 67% of children under the age of 5 prematurely succumbed to the disease [1, 2]. The currently available drugs in the market are not effective enough and there is a growing concern of reported cases of drug resistance in some parts of the world. These drugs include artemisinin combination therapy which was a promising treatment for malaria. Therefore, there is an urgent need for alternative drugs or vaccines for malaria. Among the six species of malaria causative agents namely,

*Plasmodium vivax* (*P. vivax*), *P. ovolae*, *P. malarae*, *P. yoelli*, and *P. falciparum*, *P. falciparum* is the causative agent of the deadliest form of malaria. *Plasmodium falciparum* parasites survive in the female anopheles mosquito and the human host. When the Anopheles mosquito bites a human during its blood meal, the parasite is then transferred to a human host. It is reported that the temperature in the mosquito vector is about 22°C, whereas in the human host the normal body temperature is 37°C, but when the malaria symptoms kick in, the temperature goes as high as 38°C and above [3–5]. However, these sudden temperature changes do not affect the parasite viability. The temperature changes put pressure on the physiology of the parasite because there is a group of proteins whose production increases when the parasite is exposed to human host temperature. These molecules or proteins are believed to be the housekeepers of the cellular system of the *P. falciparum* parasite. When the parasite enters the human host, it produces schizonts into the liver, they then matured into merozoite and rapture in the red blood cells, therefore invade red blood cells. This stage of the parasite life cycle is very important because this is when the parasite would then multiply, differentiate and produce more merozoite to invade red blood cells and malaria symptoms would then start to show and the human host temperature would increase above 38°C [6]. Therefore, the production of proteins called heat shock proteins steadily increases as means for parasite protection under harsh conditions or sudden change of temperature.

Heat shock proteins are ubiquitous, highly conserved molecules that occur in all recognized life forms. The constitutively expressed heat shock proteins are generally designated as 'heat shock cognate' (Hsc) forms to differentiate them from the inducible heat shock protein (Hsp) forms. The constitutively expressed forms play a housekeeping role, while the inducible forms are normally expressed in response to stress. The role of heat shock proteins is to protect the newly synthesized proteins from misfolding, which could result in the formation of inclusion bodies or truncated proteins that can be toxic to the cellular system of the parasite. On the other hand, a group of proteins known as polyamines is produced in the parasite for proliferation, differentiation, and growth. When merozoite invades red blood cells, polyamines are believed to be at the center of the parasite multiplication process and act as molecular chaperones. For example, when cells that lack polyamines are added with polyamines and exposed to a temperature above 37°C, the cells do survive [7], signifying that polyamines display chaperone activities. Wide studies conducted in plant biochemistry demonstrated that when plant cells are exposed to abiotic temperature, polyamines protect plant cells and improve growth and production [3]. In P. falciparum, it could be that polyamines do cooperate with heat shock proteins as means for the parasite to survive under harsh conditions. For example, Polyamines protected plasmid DNA strand breaks in vitro and aided the cell survival against irradiation in polyamine deficient *Escherichia coli* mutant strain [8]. It is shown that DNA strand breaks were prohibited 4–6 fold more by polyamines such as spermidine and spermine compared to putrescine and cadaverine in the dithiothreitol/Fe (III)/O2 system [9]. After UV-irradiation, the protection of DNA strand disruptions by spermine and spermidine was twofold as effective as that by putrescine and cadaverine. To measure the viability of *Escherichia coli* cells lacking polyamines, they were grown in the medium containing putrescine and spermidine. They displayed increased survivability compared to polyaminedepleted medium at a dose of 60 and 40 J/m2 . After γ-irradiation to a dose of 80 Gy, cell survivals of a mutant strain were significantly increased to 7.7- and 23.8-fold by putrescine and spermidine, respectively. Taken together these results suggest the probability that polyamines play a powerful role in the protection of DNA or cell damage by radiation. Polyamines can play an essential role in cell growth and differentiation and are also involved in the protection of cell structures [10].

#### *A Double Line of Defense: Heat Shock Proteins and Polyamines Act as Contributing Factors… DOI: http://dx.doi.org/10.5772/intechopen.98852*

In addition, reports suggest that when polyamines metabolism is disrupted, several cellular processes are affected, including transcription, translation, gene expression regulation, autophagy, and stress resistance. Some studies reported that in fact, polyamines influence the production or synthesis of heat shock proteins, even though it is not clear how this process takes place. Heat shock proteins come in different sizes and activities, whereas polyamines include putrescine, spermidine, and spermine. With *P. falciparum* having a unique biosynthesis of polyamines, for example, S-Adenosylmethionine decarboxylase is connected to Ornithine decarboxylase (AdoMetDC/ODC) has been regarded as an ideal drug target [11]. Therefore, drug development starts at the protein level, where characteristics of proteins are examined, this unique arrangement of P. falciparum AdoMetDC/ODC is regarded as an ideal drug target for malaria due to its role in the biosynthesis of polyamines in the parasite [9, 12, 13]. On the other hand, heat shock proteins such as Hsp70/Hsp40 partnership, Hsp90, Hsp110, small heat shock proteins, have been extensively studied and they have been well documented on how they keep the parasite viable, but what we do not know is how the parasite cellular system brings together polyamines and heat shock proteins as its double line of defense as a survival strategy. This is protective system is especially vital during red blood cell merozoite invasion, which is a crucial stage for the parasite's survival. This, therefore, justifies the need to understand this mysterious partnership between these two molecules towards multidrug development. In our laboratory, we are currently interested in getting answers in that direction, intending to develop alternative drugs against malaria [8, 14–16].
