Genome-wide liver transcriptomic profiling of a malaria mouse model reveals disturbed immune and metabolic responses

Abstract

Background The liver is responsible for a range of functions in vertebrates, such as metabolism and immunity. In malaria, the liver plays a crucial role in the interaction between the parasite and host. Although malarial hepatitis is a common clinical complication of severe malaria, other malaria-related liver changes have been overlooked during the blood stage of the parasite life-cycle, in contrast to the many studies that have focused on parasite invasion of and replication in the liver during the hepatic stage of the parasite. Methods A rodent model of malaria was established using Plasmodium yoelii strain 17XL, a lethal strain of rodent malaria, for liver transcriptomic profiling. Results Differentially expressed messenger RNAs were associated with innate and adaptive immune responses, while differentially expressed long noncoding RNAs were enriched in the regulation of metabolism-related pathways, such as lipid metabolism. The coexpression network showed that host genes were related to cellular transport and tissue remodeling. Hub gene analysis of P. yoelii indicated that ubiquitination genes that were coexpressed with the host were evolutionarily conserved. Conclusions Our analysis yielded evidence of activated immune responses, aberrant metabolic processes and tissue remodeling changes in the livers of mice with malaria during the blood stage of the parasite, which provided a systematic outline of liver responses during Plasmodium infection. Graphical Abstract

Evaluating the stability of host-reference gene expression and simultaneously quantifying parasite burden and host immune responses in murine malaria

“…By analysing the variability of Ct values from 12 commonly cited host reference genes, we identified half were differentially expressed following immunisation and infection, emphasising the importance of systematic reference gene assessment. Although we have established that TBP and SDHA as highly suitable for RTqPCR relative normalisation in our model of P. yoelii sporozoite challenge and adenovirus vector-based 'Prime-Target' immunization, it is likely that other stably expressed reference genes may be identifiable with unbiased screening in other models 35 – 37 . TBP and SDHA have been identified as stable reference genes for human leukocyte RTqPCR analysis studies 22 .…”

“…For example, RTqPCR can measure the transcriptional response to Plasmodium challenge of critical immunomodulatory cytokines, such as Interferon-gamma (IFN-γ), Interleukin 2 (IL-2), and Interleukin 10 (IL-10), which are associated with host-protection 32 – 34 . Unbiased RNA sequencing 35 – 37 and RTqPCR protocols 38 , 39 , have been developed to analyse mRNA responses to Plasmodium infection in whole liver, isolated splenocytes 28 and liver lymphocytes 40 . However, these protocols require additional processing, which preclude matched assessment of parasite burden, did not identify differences in critical protective immunomodulatory cytokines, or have been described following repeated or large sporozoite challenges, which may not be optimal for vaccine antigen testing.…”

Mitochondrial oxidative phosphorylation and dynamics in mouse liver infected with Plasmodium berghei and the modulatory effects of a novel compound purified from Phyllanthus amarus

“…The preerythrocytic stage of Plasmodium infection occurs in the liver and the progression of infection in the liver tissue determines the erythrocytic stage of the infection. In the cause of liver infection, there are striking evidences that there is activated immune responses, perturbed metabolic processes and tissue remodeling in the livers of mice infected with Plasmodium species (Hu et al, (2023). Apart from Plasmodium infection, there are various injuries as a result of increased parasite overload that will de nitely affect mitochondrial copy number and damage.…”