**5. Role of autophagy in the regulation of T-reg/Th17 balance in malaria infection**

Autophagy is a well-known process which plays a beneficial role against infectious disease not only by degrading pathogens but also by activating host immune system. Autophagy plays an important role in multiple aspects of immune system like cytokine balance, modulation of immune cells, innate and adaptive immunity and antigen presentation [70]. In our study we have found increased expression of *Regulation of T-reg/Th-17 Balance: One Step Closer Towards Immunotherapy Against Malaria… DOI: http://dx.doi.org/10.5772/intechopen.97045*

all five major markers of autophagy pathway viz. BECLIN1, ATG3, ATG5, ATG7, p62 with the progression of disease and the expressions were highest at 8 dpi *Plasmodium berghei* ANKA infection. An increase in the expression of LC3B has also been found. Simultaneously, the ratio of LC3B:LC3A increased at 8 dpi *Plasmodium berghei* ANKA infection which indicates the conversion of LC3A to LC3B and an upregulation of autophagic flux [71]. It has been reported that pDC harbours live *Plasmodium* parasite which have the ability to cause malaria symptoms when transferred to naïve mice [72]. Rapamycin (known autophagy inducer) treatment reduces the plasmodium load in splenic pDC. Autophagic induction increases the expression of CD205 and MHC I on pDC which stimulates antigen processing and antigen presentation respectively as compared to non-treated PbA infected group. Relative downregulation of proinflammatory cytokines like IL-6 and TNFα and positive induction of anti-inflammatory cytokines like IL10 was observed in autophagy induced mice. A tilt towards low Treg/Th-17 and high mDC/pDC ratio have been observed during malaria infection which induce Th1 pathway mediated immune regulation and poor prognosis for host. But autophagy induction can shift the Treg/Th17 balance towards increased T-reg population along with increased pDC population which can alter the mDC/pDC ratio, suppress the proinflammatory response and promote Th2 pathway [73]. Autophagic regulation of splenic red pulp macrophages show similar results in context to Treg/Th-17 balance [74]. Upregulation of proinflammatory cytokines production and alteration of Treg/Th-17 balance towards increased population of Th17 is a major cause for poor prognosis of malaria. Autophagy induction can revert the imbalance and help in betterment of host immune response.

### **6. Conclusion and future perspectives**

Despite of continuous efforts towards invention of a proper and effective vaccines for malaria prevention, very few of them have their impact on reducing the number of malaria cases and malaria induced mortality. ACT still is the major therapeutic strategy in combating this disease, although emergence of Artemisinin resistance has been a major worry for the effectiveness of ACT during treatment of malaria patients. Immunotherapeutic strategies have been quite promising in several inflammatory disorders, cancers, autoimmune disorders and other infections. In case of malaria, although immunomodulation is very effective in murine studies, causing declination of parasitemia and increasing the survival percentages, application of those immunotherapeutic strategies in human is still awaiting. The balance between two T helper cell subsets i.e. T regulatory cells and Th-17 cells has been found to be important in both lethal and non-lethal malaria and factors which regulate this balance seems to play a pivotal role in disease manifestation. Studies using murine models has been quite effective in determining the factors and how they influence the disease outcome by regulating the Treg/Th-17 balance. Among those factors, TGFβ and IL-6 directly regulate the percentage of cells, expression of their characteristic transcription factors and functional cytokines secreted by Treg and Th-17 cells. Neutralization of IL-6 has direct effect on parasitaemia and survival percentages of mice infected with *Plasmodium* sp. It also reverses the dysregulated Treg/Th-17 ratio to optimal levels and can be a target for future therapeutic interventions against malaria infection. mDC/pDC ratio also play the role of a regulator and as a bridge to control Treg/Th-17 ratio. IL-6 neutralization can also bring the altered mDC/pDC ratio to normal levels. Apart from these, autophagic regulation of dendritic cells and macrophages in the spleen has its effect on Treg/Th-17 balance. Though, use of T-regulatory cells and drugs that directly

regulate the altered ratio is regarded as a potentially attractive therapeutic strategy in autoimmune disorders, application of these approaches in malaria and other parasitic infections needs more attention and caution. Further investigations are still required to achieve the goal of a malaria free world.
