How viruses help us understand the way our immune system works

October 31, 2016

VIRUSES

Viruses are small infectious particles which cannot replicate on their own. They are therefore dependent on other living cells with their life cycle and replication. Viruses infect all types of cells including bacteria, plants, fungi and animals. However, some viruses have evolved to infect only a limited number of hosts, for example a virus causing smallpox, Variola virus (figure 1), can infect and survive only within human cells. Other viruses, on the other hand, infect various species and thus they persist within a broad range of the hosts.


Figure 1: Variola virus



SMALLPOX - a threat of humans defeated

One of the oldest documented evidence of smallpox infection comes from the mummified remains of Ramses V (1157 B.C., figure 2). In 16th century smallpox was imported into America where it swept through the continent and took lives of millions of Native Americans. By 18th century, smallpox became a leading cause of death within the growing population across the world. Despite the advances in the health care in 20th century, there was no cure for smallpox yet discovered and smallpox was responsible for millions of deaths.

Smallpox was highly contagious, serious and sometimes fatal disease with characteristic pimples on the skin. In 1796, Edward Jenner (figure 3) observed that infection with a virus causing cowpox in cattle had protected milkmaids from a serious smallpox infection. Even though it was an imperfect vaccine, it helped to save countless numbers of lives. Furthermore, it started the attempts to fight with and eliminate smallpox by vaccination. Indeed, Variola virus was declared eradicated in 1980 (figure 4); however, several stocks of the live virus are securely kept in two laboratories, in the USA and in Russia, respectively, where scientists further study the virus.


Figure 2: Ramses V





Figure 3: Edward Jenner



Figure 4: Eradication certificate



VACCINIA VIRUS – a harmless cousin

Vaccinia virus is closely related to smallpox and cowpox viruses. In contrast to smallpox, vaccinia infection is mild or even asymptomatic, however, the host immune response to vaccinia is strong enough to protect individuals against smallpox infection. Therefore, vaccinia has been used as a safer vaccine against smallpox for the last decades.

Unlike most viruses, both variola and vaccinia are unique large DNA viruses which are almost independent of the host cell. Their genomes contain genes for replication, transcription as well as for immune evasion. Due to its similarity to smallpox, vaccinia is a widely studied virus in many laboratories. Furthermore, with the advances of molecular biology, vaccinia genome is often used as a transport vehicle for vaccine against other diseases.


ANTIVIRAL STRATEGY OF THE HOST

Viruses are the most abundant and rapidly evolving pathogens and as such they represent a constant challenge for the host. The ability of the host cells to detect viruses and to trigger antiviral immune response is crucial for the survival of the cell and of the host. For this reason, the host cells developed a number of specialised molecules which recognize conserved structures of pathogens and/or abnormal forms of nucleic acids (figure 5).



Figure 5: Cartoon illustrating function of TLRs.


Such molecules are for example Toll-like receptors (TLRs) which comprise a family of at least 10 specialized receptors. All TLRs share a common motif that can be found in some plants as well as insect proteins thus having a crucial function in immune defence across different kingdoms. TLRs can be localized on the surface of the cells (TLRs 1/2, 4, 5, 2/6) or inside the cells (TLRs 3, 7, 9). TLRs detect microbial structures that are foreign to human cells, such as microbial lipopetides and proteins, or viral double-stranded RNA (figure 6). After their activation, TLRs start the innate immune signalling that leads to activation of interferons and pro-inflammatory cytokines. This activation triggers an adaptive immune responses and subsequently leads to elimination of the pathogen.

         
 Figure 6: TLR receptor which detects viral RNA





VIRAL IMMUNE EVASION STRATEGY

Figure 7: Schematic of viral infection of a host cell.


Viruses aim to invade host cells without activating antiviral immune defence of the host cells (figure 7). Therefore viruses have evolved specialized proteins which enables them to evade or to subvert the host immune responses at multiple steps. They can either inhibit immune responses unfavourable to the virus and/or stimulate favourable outcomes which contribute to their persistence. These mechanisms are of major interest to scientists because they can contribute to our understanding of the viral pathogenesis and give us further insight into the function of the host immune pathways.

For example, two proteins encoded by Vaccinia virus, namely A46 and A52, have been shown to modulate the immune response during a vaccinia virus infection. A46 targets TLR4 signaling by disrupting interaction with downstream adaptor proteins and thus it inhibits both pro-inflammatory and interferon responses. In contrast to A46, A52 has two faces. On one hand, A52 stimulates production of anti-inflammatory cytokines while, on the other hand, it strongly inhibits the pro-inflammatory response. Importantly, the function of A46 and A52 is not redundant but it is rather complementary suggesting their unique function during infection.


FUTURE IMPLICATIONS

Altogether, clarifying the mechanisms by which viruses inhibit and manipulate host immune responses has two main implications. First, it tells us more about viral pathogenesis which subsequently leads to identification of virulence factors as well as novel drug targets. Secondly, study of viral evasion and subversion can identify key molecules and new mechanisms of the host immune responses. All these findings will be eventually used for a new drug development which will specifically modulate viral as well as host proteins to suppress inappropriate signalling or to treat chronic infections.