Rick Tarleton
9.5 Regulation of immune responses and parasite persistence
stage of the infection, and provides additional corroboration that the immune system is successful in the long-term control of the infection.
Although the size and effectiveness of the anti-T. cruziCD8+ T cell response attests to its high effectiveness, the initial generation of the response appears to be significantly delayed, relative to that seen in many other infections. This observation is consistent with the evidence, discussed above, that the infec- tion byT. cruzi is relatively silent due to the absence of strong triggering of innate responses.
9.4.3 Humoral immune responses
Antibody responses during T. cruzi infection have often been characterised as non-specific (polyclonal), but this is not uniformly the case. It may simply reflect the vast number of antigen variants that T. cruzi presents to the im- mune system through an array of multigene families of surface proteins such as the ts, mucins, and mucin-associated proteins (MASPS). Transfer of serum, or antibody fractions of serum from infected animals, provides significant (al- though not total) protection to infection in na¨ıve animals. Furthermore, ani- mals lacking B cells are highly susceptible to infection although, interestingly, mice lacking B cells due to a knockout in the mu immunoglobulin heavy chain (MT) are able to control acute infections somewhat longer than do mice lacking CD8+ T cells before eventually succumbing to the infection with very high parasitaemias.
The mechanism of antibody-mediated control ofT. cruziinfectionin vivois not fully understood, but anti-T. cruziantibodies have been demonstrated to par- tially block host cell invasionin vitro, to facilitateT. cruziuptake by phagocytic cells and to induce complement-mediated and complement-independent lysis ofT. cruzi(Figure 9.3).
Two rather unique reported activities in the pool of lytic antibodies induced byT. cruziinfection are anti-galactosyl antibodies that lyseT. cruziwithout the participation of the classical or alternative complement pathway, and antibod- ies against a complement regulatory protein (CRP) that act by preventing the normal decay-accelerating factor-like activity of this CRP (see Chapter 1), in turn facilitating complement lysis ofT. cruzi parasites. These lytic antibodies have been suggested as good markers of spontaneous or drug-induced para- sitological cure inT. cruziinfection
9.5 Regulation of immune responses
4 1
2
Anti-CRP antibodies
3
Anti-galactosyl antibodies
PARASITE LYSIS Fc-mediated PHAGOCYTOSIS
Antibody-mediated BLOCKING OF INVASION
CRP COMPLEMENT-MEDIATED LYSIS OF PARASITES Macrophage
HUMORAL RESPONSES TO TRYPANOSOMA CRUZI
Figure 9.3 Antibodies help to control extracellularT. cruzitrypomastigotes in several ways.Opsonised T. cruzitrypomastigotes are not able to invade new cells (1) and are a target for
macrophage-mediated phagocytosis (2). Furthermore, anti-galactosyl antibodies which recognise mucin-like GPI-anchored glycoproteins on theT. cruzisurface mediate both complement-dependent and independent parasite lysis (3). Lastly, antibodies are generated inT. cruziinfection, which recognise and neutralise complement regulatory protein, in turn facilitating complement-mediated lysis of parasites (4). The relative sizes of the parasites and cells have been equalised for illustrative purposes but, in reality, the Trypanosomes are much smaller than macrophages or muscle cells.
Abbreviations: CRP, complement regulatory protein.
effective and, if abrogated, lead to overwhelming parasite expansion. Among the best examples of the latter are cases of HIV exposure in individ- uals with chronic T. cruzi infection. The rapid and dramatic impact of cyclophosphamide-mediated immunosuppression in mice, in which unde- tectable levels of parasites become an overwhelming infection in the span of just three weeks, also emphasises just how effective the normal host immune response is in controllingT. cruziinfection (Figure 9.4). Nevertheless, immu- nity toT. cruziis also rarely effective in completely clearing the infection – what is the reason for this?
The subtle character of early invasion and expansion ofT. cruziin host cells argues that the identifiedT. cruziPAMPs (e.g. GPIs and DNA) are well-hidden on the invading parasites. The ability to avoid innate responses would account for successful initial establishment of the infectionin vivo, but perhaps not for the long-term persistence ofT. cruziin the face of the vigorous adaptive im- mune responses that are generated. In experimental models or human infec- tions, it is difficult to find strong evidence of classical regulatory mechanisms
Figure 9.4 Inflammation correlates with control of parasite load.(Top) Histology sections from skeletal muscle of mice infected withT. cruziCL strain at 240 dpi. (Bottom) Sections from mice infected withT. cruziCL strain at 15 days post-immunosuppression with
cyclophosphamide. Note the absence of inflammation and the presence ofT. cruziwithin muscle cells (arrows) following immunosuppression during the chronic infection.
Scale bar: 200 mm (photo credit: Juan Bustamante).
(e.g. regulatory T cells or a high level of production of regulatory cytokines) that might thwart the effectiveness of anti-T. cruziimmunity. The fact that the anti- T. cruziCD8+ T cell response is one of the most potent of such responses ob- served in any infectious disease is also a strong indication that immunoregu- latory mechanisms are not a dominant force in the overall course ofT. cruzi infection in most hosts.
Particularly in the chronic infection,T. cruziwould appear to spend the ma- jority of its time inside host cells during its 4–5 day replication cycle, and relatively little time in the circulation, where antibodies appear to be highly effective in killing the extracellular trypomastigotes. How these intracellular parasites within muscle or fat cells evade the potent anti-T. cruziCD8+ T cell response is not clear. The fact that ts peptides are the primary targets ofT. cruzi- specific CD8+ T cells has attracted attention in this respect. The ts family is greatly expanded to thousands of genes inT. cruzi, compared with a handful of genes in other related kinetoplastids, suggesting that some strong evolution- ary pressure has been exerted on this gene family. The mechanism by which the simultaneous expression of many ts proteins and the variant ts-encoded epitopes encoded by this gene family might facilitate immune evasion and par- asite persistence is still unknown.