Sweet rejection: sugar-coated malaria parasite

Life is a competition, even for a parasite like a malaria. To infect the host the parasite needs to overcome not just host's defense system but to out-compete the local resident micro-flora as well. 

This new paper in Cell is a thorough research about the initial events of of malaria infection and the role of sugar molecules, called glycans, in the host defense against malaria.

It is well-known that hosts and their parasites may share molecular signature. Blood types, ABO system is one such example. Burnet's clonal selection theory predicts that any such similarity between host-pathogen prevents the host to mount an efficient immune response against shared antigens. As a consequence, based on pathogen burden and evolutionary pressure, the hosts started to loose the capacity to express such shared molecules.

It appears that at some point in their evolution human ancestors lost the capacity to make one type of sugar, alpha-gal, expressed by malaria. This change conferred an improved capacity to defend against malaria. 

This papers shows how exactly such modification provided protection. It turns out to be dependent of natural immunization conferred by gut resident microbes expressing the same exact sugars.

Analysis of serum samples across different age group from children in Mali (malaria endemic region), the authors noticed a gradual increase in anti-alpha-gal IgM level over time. Interestingly, 6-months parasite free condition correlated with higher level of anti-alpha-gal IgM in the serum.

To study this observation in laboratory setting, the authors used mice deficient in the capacity to make alpha-gal (alpha-gal KO). This "human-like" mice can produce anti-alpha-gal antibodies upon colonization with alpha-gal-positive E.coli O86:B7, but not alpha-gal-negative E.coli K12 strain. 

The authors showed that colonization of alpha-gal KO mice with alpha-gal-positive E.coli O86:B7 provided a protection against malaria transmission.

This protection after gut flora colonization was conferred by soluble germ-line, non-mutated IgM.

Immunization of alpha-gal KO mice with  (a) alpha-gal conjugated to BSA (protein carrier) or (b) rabbit RBC (naturally expressing high levels of alpha-gal) conferred protection against malaria transmission.

Deep analyses of mechanism of protection after immunization revealed it was dependent on T cell help and on both IgM and IgG (of note, immunization with rabbit RBC conferred protection even in IgM-deficient mice, unlike protection conferred after colonization with alpha-gal expressing E.coli O86:B7).

The protection could be conferred by passive transfer with IgM, IgG3 and IgG2b, but not IgG1 and IgG2a.

In summary, this study provides evidence how gut flora affects host's defense against parasites by a way of natural immunization. Of course, it is remains to be determined whether immunization against alpha-gal will protect humans as well as it does for "human-like" mice.

David Usharauli

     

   

  

When more is less: gut IgA prevents maturation of natural IgM immunity

This is a very interesting and thought-provoking study from journal Immunity. It focuses on immunobiology of gut associated follicular T helper (TFH) cells. This is a subset of helper T cells that is designed to provide necessary signals to germinal center (GC) B cells to produce high-affinity antibodies.

The authors study the role of P2rx7, a purinergic, ATP-activated receptor 7 on gut TFH function. Initially, the authors made an observation that P2rx7 is selectively and highly expressed on TFH. 

Interestingly, P2rx7-KO mice harbored increased number of TFH in peyer's patches (PP).

This increase in TFH cells in P2rx7-KO mice was cell-intrinsic since it was observed in CD3KO recipient mice adoptively transferred with 1:1 ratio of WT or P2rx7-KO PP T cells. 

Co-housing and co-(cross)-fostering experiments showed that effect of P2rx7 deficiency on TFH was independent of a any unique gut flora present in P2rx7-KO mice (though better experiments would have been to compare P2rx7-KO mice on Germ-Free (GF) background or test WT and P2rx7-KO mice from the same littermates).

Next, the authors found that greater presence of TFH in P2rx7-KO mice was linked to a reduced sensitivity of TFH to cell death in absence of P2rx7.

Additional experiments revealed that P2rx7-KO mice harbored more IgA producing cells in the gut (small intestine), but fewer IgM producing cells in the serum.

A scanning electron microscopic examination of small intestine revealed dramatic reduction of SFB colonization in P2rx7-KO mice.

Finally, series of in vivo experiments with cecal ligation and puncture (CLP) showed that P2rx7-KO mice were highly sensitive to death after sublethal CLP and they could be rescued with serum IgM injection from WT mice.

In summary, the data in this paper suggest that overzealous gut TFH function in P2rx7-KO mice contributes to the decline of the serum level of natural IgM and subsequent reduction of the host fitness in response to systemic inflammation.  

Some questions remains to be answered: 

(a) Why are gut TFH cells but not spleen or LN TFH cells sensitive to ATP? 

(b) Why gut IgA cannot compensate for serum IgM?

(c) If TCR signaling makes WT TFH refractory to ATP mediated cell death, does it mean that P2rx7-KO mice generate an excess of antigen non-specific TFH but not antigen-specific TFH compared to WT mice? In other word, does ATP controls antigen-(commensal)-specific TFH development?

David Usharauli

    

Great illusion: helminth-virus co-infection

This is a second paper in a series that examined the effect of co-infection on body's immune response. 

This one came from David Artis' lab (though both papers have another senior author H.W. Virgin, who by the way has just published another two papers in journal Science).

David Artis is a quite prolific scientist in immunology. This paper is well done indeed. Simple and complete. That's why it was accepted for publication in Science within 1 month of submission (a quite an achievement :)

Here too, the authors study the outcome of anti-viral immunity (TH1 response) in presence of helminth infection (TH2 response). 

Initial data showed that both CD8 and CD4 T cell responses to mouse norovirus were diminished in presence of Trichinella Spiralis larvae (TH2 activator). 

Not just overall magnitude of anti-viral CD8 T cell response was reduced but even CD8 T cell poly-functionality and CD4 T cell response were impaired in presence of Trichinella infection. In addition, helminth infection led to increase in viral replication in the gut. 

This reduction of anti-viral immune response were observed in studies using a different virus, Flu virus expressing LCMV gp 33 protein and a different helminth infection (Hp). 

Furthermore, this modulation of anti-viral T cells response and viral replication by helminth were apparent even in germ-free mice, indicating that it was gut microbiome independent process. 

Mechanistically, this modulation of viral immunity by helminth was mediated through STAT6 and IL-4ralpha and TH2 signature molecule Ym1 (I will call it ya-me 1). 

In summary, this paper clearly and unequivocally showed that helminth (worm) co-infection diminishes anti-viral T cell response and as a consequence promotes viral replication in target tissue.

In my opinion, this paper is great but has totally missed one critical point. It absolutely does not matter how much helminth infection affects the particular readout of immune response measured or how much it promotes viral replication, unless one shows that this modulation has any detrimental biological effect on the host. however, both papers failed to provide any guide as to the measure of tissue pathology (did increase in viral replication cause more tissue damage? What about antibody response?). Without such information, however, the data are just nice but irrelevant.

David Usharauli