-Prerna Jha, NIT Durgapur
Microbes Vs. Pathogens
Organisms that are of microscopic dimensions are simply referred to as microbes. They are so individually so tiny that we often need the help of microscopes (laboratory devices with high power lenses) to see them with our naked eyes! But not all of them are harmful. Pathogens constitute a diverse range of microbes consisting mainly of viruses, bacteria, and also some unicellular and multicellular eukaryotes that possess the ability to cause disease.
Microbes usually need host microbes or larger organisms to live. They not only depend upon their hosts for nutrition and survival but some even possess the ability to utilize the host’s cellular or molecular machinery to carry out various necessary processes that it otherwise can’t execute by itself due to lack of such complex or “sophisticated” machinery.
Although some of such microbes may cause damage by virtue of their virulence inside the host’s body, others may be friendly, in the sense that their interaction with the host is synergistic(mutualistic/symbiotic) or commensalistic. Similarly, we humans also host a very active pool of microbes, referred to as our microbiota, which is generally beneficial to us (probiotic).
The sequencing of the human genome shows evidence of microbial remnants in our DNA which might have evolved from our primitive ancestors and eventually got passed down from generation to generation, to get “fossilized” in our genome today.
Our “Second” Genome
The gut microbiome also referred to as the ‘second genome’, has been an active area of research in finding relation to human ancestry and for predicting potential cures for various diseases. This is due to the presence of a huge number and variety of microbes in our gut that live in harmony with our body and are accustomed to its functions. These microbes play an influencing role in shaping our immune system and controlling brain development and social interaction through bidirectional communication between the gut and brain. A majority of these are bacteria, which form a part of the unconscious system and also regulate our emotional behavior. They can produce several neuroactive compounds inside our bodies. The brain in turn allows our bodies to provide them with nutrition for their survival.
A team of researchers at Babraham Institute, near Cambridge, UK, discovered that certain bacteria in our gut lining increase chemical markers that affect histone crotonylation (epigenetic modification) on the surface of our genes, by silencing a protein named HDAC2. This is linked to an increased risk of colorectal cancer. This epigenetic factor thus could alter gene activity by turning genes off or on and hence are important for preventing cancer.
Bacteria Modifying Our Genome
Many of the human genes have been found to be homologous to bacterial genes. It has been seen that often the bacterial DNA from a mother gets carried to her offspring. That’s the reason why mitochondrial DNA (mtDNA), being smaller in size and possessing maternal lineage of chromosomes is preferred over nuclear DNA to trace the ancestry of someone.
A few studies based on rodents concluded that the absence of a specific bacteria could substantially cause alterations in their immune response patterns. This is generally only possible if genetic mutations occur in the host organisms (here, the rodent), but surprisingly it was happening because of certain key genes that the bacteria possessed. Hence naturally, their absence brought about critical health issues and behavioral changes in the rodents. One such example is that the test rodents displayed autistic-like behavior due to altered social behavior.
To date, laboratorical modifications in synthetic oligonucleotides of DNA were brought about by adding sulfur to the sugar-phosphate backbone to make DNA resistant to nucleases. In a recent study conducted by a team of researchers at the Massachusetts Institute of Technology (MIT), it was seen that a cluster of bacterial genes referred to as ‘dnd gene cluster‘ could allow them to carry out these modifications on their own. Since these modifications manifest naturally, studies based on qualitative or descriptive approaches are deemed necessary as it might open an avenue towards a new approach in providing gene and antisense therapies of human diseases.
Bacterial pathogens like viruses have often been known to reprogram their host cells’ genetic mechanisms, Besides the cells getting infected, these pathogens may also bring changes in the host cell’s gene expressions in unaffected cells, in the following paracrine manners:
● Bacterial virulence factors bring about changes in the host gene expression by chromatin remodeling. This involves the prevention of histone phosphorylation by OspF, a Shigella type III effector. OspF could alter the overall immune response as it could hinder the activation of MAPK, further inhibiting the interaction of NF-κB to certain promoter regions such as that of the IL-8’s; Histone deacetylase activity in correlation with suppression of interferon response was influenced by Mycobacterium tuberculosis. Both these factors tie in with decreasing transcription activity of our immunity genes.
● Certain bacterial toxins like those of E. coli cytotoxic necrotizing factor can activate Rho-family GTPases leading to Rho-dependent mitogenic signals and the formation of multinucleated giant cells.
● Some toxins released by Clostridium botulinum may also cause cell cycle arrest, preventing the maturation of epithelial cells while promoting bacterial colonization.
Recent research reveals a phenomenon of lateral gene transfer(LGT) from bacteria to human somatic cells, pronounced mainly in those involving a tumor rather than in healthy cells. It is inspected that this phenomenon would open new insights into cancer study and other diseases involving DNA damage and mutations.
Viruses Modifying our Genome
In contrast to other pathogens which may or may not depend completely upon host cells for nutrients, viruses are obligate pathogens that completely rely upon host cell machinery for survival and reproduction. Upon entry into our cells, their main target is to hijack the host cell’s molecular machinery in a way that makes the ribosomes synthesize more of the viral proteins instead of their own, eventually spreading the disease to different cells, then tissues, and organs.
They affect the transcription of host cells, by encoding proteins that block the splicing and polyadenylation of mRNA transcripts, as can be seen, to be performed by Influenza viruses; proteases which cleave the TATA-box binding factors, as observed in Poliovirus. In some cases, the 5′ cap of the host cell mRNA is cleaved by some endonucleases encoded by the viruses, disabling their recognition by the transcription initiation factors, thereby preventing host cell transcription.
Inheriting and passing on foreign DNA
Retroviruses possess the capability of converting their RNA genome into a dsDNA upon entry into their host cells, due to the presence of an enzyme called reverse transcriptase. They can further integrate their genome into that of ours and continue to produce a factory of viral particles by taking over the host cell machinery.
The most common example of such retrovirus we encounter nowadays is the SARS-CoV2 virus causing Covid-19.
If the cell infected by the virus turns out to be a germline cell, these viral genomes, rather the portions that got integrated into the host’s genome become heritable. These then get carried onto further generations, just like the viruses which contaminated our ancestral DNA must have evolved to attain fixtures in our DNA, nearly constituting 8% of the human genome today and are called endogenous retroviruses (ERV). Though these viral DNA’s have become fossilized and somewhat non-functional, our cells have repurposed those viral genes to carry out multiple functionalities in our body, to contribute to our immune system’s various functions.
Conclusion
Studies are pointing in the direction that it’s not only the host cell’s genetic material but also those from the bacteria and viruses, whom we otherwise refer to as the ‘villains of health’, that are getting inherited to the offspring. And this phenomenon often plays a critical role in shaping our immune system and health in general. These pathogens and their host-pathogen interactions have been a constant area of research to trace human evolution, the phylogeny of genetic variation, and in figuring out the mechanisms of various diseases.
Also read: DNAzymes – a therapeutic tool
Sources:
- Nhieu, G. T. V., & Arbibe, L. (2009). Genetic reprogramming of host cells by bacterial pathogens. F1000Prime Rep, 1(80). https://facultyopinions.com/prime/reports/b/1/80/
- K. Storr (2015). Can bacteria affect our DNA? World Economic Forum. https://www.weforum.org/agenda/2015/02/can-bacteria-affect-our-dna/
- Babraham Institute. (2018) How good bacteria control your genes: Chemical signals from gut bacteria influence gene regulation in the gut lining. ScienceDaily. https://www.sciencedaily.com/releases/2018/01/180109102758.htm
- Massachusetts Institute Of Technology (2007) Bacteria Employ Type Of DNA Modification Never Before Seen In Nature. ScienceDaily. https://www.sciencedaily.com/releases/2007/12/071203142430.htm
- Institute of Medicine. (2011). What you need to know about infectious disease. National Academies Press. https://doi.org/10.17226/13006
- Balloux, F., & van Dorp, L. (2017). Q&A: What are pathogens, and what have they done to and for us? BMC Biology, 15(1), 91. https://doi.org/10.1186/s12915-017-0433-z
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