genomewide characterization of host-pathogen interactions by ...

Maren Depke
Discussion and Conclusions
induced APOL1 belongs to the group of BH3-only proteins which achieve their apoptotic effect by
binding to proteins of the Bcl-2 family. It is discussed that the apoptotic effect is mediated by a
mechanism of activating pro-apoptotic members of this family or inactivating pro-survival
members in a de-repression mode (Bouillet/Strasser 2002, Adams 2003, Fletcher/Huang 2006).
Accumulation of apolipoprotein L1 leads to autophagy (Wan et al. 2008, Zhaorigetu et al. 2008)
and is postulated to be linked to apoptosis (Vanhollebeke/Pays 2006). APOL genes were reported
to be induced in proinflammatory environment (Smith/Malik 2009). Unlike the secreted APOL1,
the other four induced apolipoprotein L genes APOL2, APOL3, APOL4, and APOL6 do not possess
a secretion signal peptide and therefore are thought to be localized intracellularly (Duchateau et
al. 1997, Page et al. 2001). Like APOL1, they also contain BH3-domains and are supposed to be
associated with programmed cell death and immune response (Liu Z et al. 2005).
Most interestingly, a second function of APOL1 as human serum factor which lyses serumsensitive
Trypanosoma species was identified (Vanhamme et al. 2003). After uptake, APOL1
forms pores in the trypanosomal lysosomes, and the subsequent lysosomal disruption leads to
killing of the parasite (Pérez-Morga et al. 2005). The species Trypanosoma brucei rhodesiense is
serum-resistant. Its antagonistic protein SRA targets APOL1, inhibits the lytic function, and thus
helps the pathogen to evade the immune response (Xong et al. 1998, De Greef et al. 1989,
Lecordier et al. 2009).
The APOL1 domain which is responsible for APOL1-SRA binding is called SID, and the other
APOL proteins exhibit homologous regions to this domain. The region was subjected to rapid
evolution in all six APOL proteins, and another region – called MAD – evolved rapidly only in
APOL6. The authors Smith and Malik predict from these results the existence of further unknown
antagonists to these regions, especially in intracellular pathogens, which might take advantage
from inhibition of host cell death (Smith/Malik 2009).
At the 6.5 h post-infection time point, S9 cells induced the expression of several chemokines
and cytokines. This set included CCL2 and CCL5, CXCL10, IFNB1, IL6, IL12A and others, and was
interpreted as a pro-inflammatory response. Literature references also report the induction of
chemokines/cytokines by epithelial cells after a challenge with S. aureus with the aim to recruit
immune cells and activate innate and adaptive immune responses (Moreilhon et al. 2005,
Peterson ML et al. 2005). Also endothelial cells exhibit a similar response to infection with
S. aureus (Matussek et al. 2005). The induced chemokines/cytokines from this study and the
published references overlap partly (e. g. IL6, IL15), but still contain specifically regulated genes.
The experiments were performed with different S. aureus strains. They probably influence the
host gene expression to a different extent depending on their differing repertoire of virulence
factors as it was shown for different S. aureus strains infecting endothelial cells (Grundmeier et
al. 2010), and – more distantly related – also in plasma cytokine profiles of patients suffering
from Gram-positive or Gram-negative sepsis and in microarray data sets of LPS or heat-killed
S. aureus Cowan ex vivo stimulated whole blood samples (Freezor et al. 2003). Possibly also the
different host cell lines have different specificities for the induction of pro-inflammatory
cytokines. Despite the difference, in conformity between the different studies the epithelial cells
were recognition sites for infection and mediators of this information to the immune system.
Since the effect was very explicit they were even termed to be components of the innate immune
system (Peterson ML et al. 2005).
Infected S9 cells effectuate a clearly immune defense associated transcriptomic response to
infection. Interestingly, more than 100 genes of the infection-regulated set in S9 cells were also
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