Human Codon Usage: The Genetic Basis of Pathogen Latency

Abstract

Infectious diseases pose two main compelling issues. First, the identification of the molecular factors that allow chronic infections, that is, the often completely asymptomatic coexistence of infectious agents with the human host. Second, the definition of the mechanisms that allow the switch from pathogen dormancy to pathologic (re)activation. Furthering previous studies, the present work (1) analyzes the frequency of occurrence of synonymous codons in coding DNA, that is, codon usage, as a genetic tool that rules protein expression; (2) describes how human codon usage can inhibit protein expression of infectious agents during latency, so that pathogen genes the codon usage of which does not conform to the human codon usage cannot be translated; and (3) frames human codon usage among the front-line instruments of the innate immunity against infections. In parallel, it is shown that, while genetics can account for the molecular basis of pathogen latency, the changes of the quantitative relationship between codon frequencies and isoaccepting tRNAs during cell proliferation offer a biochemical mechanism that explains the pathogen switching to (re)activation. Immunologically, this study warns that using codon optimization methodologies can (re)activate, potentiate, and immortalize otherwise quiescent, asymptomatic pathogens, thus leading to uncontrollable pandemics.

Integrating tDNA Epigenomics and Expression with Codon Usage Unravel an Intricate Connection with Protein Expression Dynamics inTrypanosoma cruzi

“…Trypanosomatids have fewer copies of tRNA genes (fewer isodecoders) (Figure 2A) than vertebrates (74,75), suggesting that these genes may be under selective pressure to avoid deleterious mutations. Here, we detected forty-six anticodons for sixty-two codons (Figure 2D and Supplementary Table 2B), which contrasts with findings in humans, where there are fifty-seven anticodons for sixty-one codons (76,77). This indicates that the parasite needs to employ more strategies to recognize the entire codon repertoire of the genome, such as employing more modifications in anticodons and codonanticodon wobble pairing.…”

Nucleotide Sequence Sharing between the Human Genome and Primers for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Detection

“…Defining the relationship(s) between infectious agents and the human host is a crucial topic in immunology, microbiology, and infectious medicine. Although it has been proposed that genetic factors might play a role, 1 2 the exact mechanisms of chronic infections and occasional (re)activation of pathogens in the human host are largely misunderstood and poorly studied. The issue became even more relevant in light of the recent Ebola virus, Dengue virus, and SARS outbreaks associated with high morbidity and mortality.…”

The Role of Codon Usage, tRNA Availability, and Cell Proliferation in EBV Latency and (Re)Activation

“…According to this molecular mimicry–oriented paradigm, the research rationale of the present work is based first on the consideration that, due to the numerous peptide commonalities, inhibition of pathogen protein synthesis during latency may represent a host device to avoid potential destructive autoimmune cross-reactions. 30 In the case in point, constraining the expression of EBNA1 would prevent the host immune response against the EBNA1 protein as well as cross-reactive reactions with the host proteins that share peptide sequences with the virus, 27 28 29 thus possibly explaining why EBNA1 protein synthesis is repressed.…”

“…Second, this study searches for possible mechanisms underlying the inhibition of EBNA1 protein synthesis on the basis of previous data [30][31][32][33] that suggested that the synthesis of a protein does not occur if the codon usage of the open reading frame (ORF) coding for the protein does not comply with the codon usage of the host. In this regard, data were obtained for the ORFs coding for (re)activation-related proteins from Herpes simplex virus type 1, 30 Toxoplasma gondii, 30 Plasmodium falciparum, 30 Cryptococcus neoformans, 30 Cytomegalovirus (CMV), 31,32 and severe acute respiratory syndrome coronavirus 2. 33 Therefore, as a logical extension of such data, the issues of why and how EBNA1 protein synthesis is restricted/resumed during latency and (re)activation, and the role of EBNA1 GAR have been analyzed through the lens of the compliance to the human codon usage.…”