Humans often fall victim to bloodstream bacterial
infections, with E. coli frequently being
the bacteria responsible. However, your sex may determine if you contract a
bloodstream bacterial infection, and the extent of its severity. It’s been
documented that females, though more likely to be exposed to E. coli, generally endure less severe
effects than men (Shröder, et al., 1998; Klein & Flanagan, 2016). In terms
of immune responses, Kupffer cells are macrophages in the liver often
responsible for selectively catching these bacteria. Complement opsonization
assists to induce the phagocytosing of the bacteria, ultimately killing it. Not
much is known about whether or not antibodies also help in this process, the
topic the researchers investigate in the paper.
The researchers intravenously injected bioluminescent E. coli strain Xen 14 (henceforth
referred to solely as “E. coli”) into
both male and female mice. They also injected mice without complement component 3 (C3-/- mice) in order to test the effects on a system without the
complement. They found that for wild type (WT) mice, Kupffer cells from females captured significantly more
bacteria in the first few minutes than Kupffer cells from males (Figure 1d,
1e). In the C3-/- mice, while Kupffer cells in females could catch E. coli roughly as easily as WT mice, Kupffer
cells in males couldn’t catch much E.
coli at all (Figure 1h). These females were also able to survive from the
infection long than males, who all died within two days (Figure 1j). This all demonstrates a sex bias in the capturing of E. coli by Kupffer cells. Males need a functioning complement for
capturing to be successful while females do not.
 |
| Figure 1. Sex-biased differences in the capture of circulating E. coli by Kupffer cells. d, Time-lapse analysis of E. coli captured by Kupffer cells (n=8) or female (n=5) WT mice. e, Intravital imaging analysis showing the amount of captured E. coli per field of view (FOV) at 2 or 10 min post infection (n=17 male mice; n=15 female mice). h, Time-lapse analysis of bacterial capture in C3-/- mice (n=3 per sex). j, Survival analysis of C3-/- mice infected with E. coli (n=8 per group). Figure and legend from Zeng et al., 2018. |
The researchers wanted to know why females could quickly
capture E. coli. When they
preimmunized male C3-/- mice, they were better able to catch
bacteria than WT mice, suggesting bacterial capture by Kupffer cells is
accomplished with the help on an antibody. By conducting flow cytometry and
isolating the isotypes, the researchers determined the antibody isotypes to be IgG3
and IgM. These isotypes are often seen in innate antibodies, and so the
researchers speculated the antibodies associated with Kupffer cells capture may
be naturally occurring (they also tested for this and found it to be true). In
addition, they found that as female mice age they have more of the E. coli antibodies, until a certain
point when the amount plateaus (Figure 5a, 5b). This suggests a connection with
puberty, specifically, the sex hormones involved in puberty. By comparing
antibody production in various groups of mice, the researchers figured out the
sex hormone involved is estrogen.
 |
| Figure 5. Estrogen elicits production of innate anti-E. coli. a, b, Flow cytometry showing serum IgG and IgM against E. coli X14 in female C3-/- (a) or female WT mice (b) at the indicated ages. Figure and legend from Zeng et al., 2018. |
Next, the researchers wanted to see if the reason for estrogen
playing a role in making the antibodies is so that females can pass the
antibodies to their children, giving them immunity – an evolutionary strategy. They
found that IgG antibodies to E. coli are found in both infant male
and female mice and not in infant mice born to antibody-deficient female mice.
The researchers then focused on specificity. They looked at a
few strains of bacteria but the only one that the antibodies significantly
responded to was enteropathogenic Escherichia
coli (EPEC). EPEC leads to diarrhea in infants and children and causes in 1.3
million children deaths every year (Ochoa & Contreras, 2011). This high
specificity in response is quite unusual for natural antibodies. With more
tests, the researchers determined that the antibodies recognized the antigen
LPS-O127, and with high affinity. They also found IgG antibodies to LPS-0127 in
human breast milk and infant serum. I found this interesting since we usually
think of IgA isotypes being in breast milk. However, this isn’t always the case.
To summarize, estrogen-driven antibodies with a high
affinity for LPS-O127 help Kupffer cells capture EPEC. The antibodies arose in
female mice during puberty and may be passed to infants via milk. These
findings are important. As mentioned above, EPEC affects many children. However,
the bacterium is uncommon in infants that were breastfed (Morrow & Rangel, 2004). Learning
more about our immune response to bacteria can help to ultimately drive the
number of infected individuals down, as we target our prevention and treatment
techniques, which may even include encouraging breastfeeding. Also, because
Kupffer cells capture the bacteria so quickly and effectively, the findings could be interesting for vaccine and antibody therapy design.
In terms of where to go next, the researchers only tested
these antibodies with a few strains of bacteria. In the future, they could test
to see if they react to more species. Further research in the role of
antibodies and bloodstream bacteria is also needed. Finally, the paper mentions
that because these are naturally occurring antibodies, cross reactivity to
self-antigens could potentially lead to autoimmune diseases in women. Personally, I think more research
should go in this direction, as it would involve a sizable proportion of the population. All in all, the research in this paper was really thorough.
They started with some findings and kept exploring to see where the next
step would lead. It appears that this is a topic that could use more research.
The effects of more research could truly change how we view innate
immunity.
References:
Zeng, Z., Surewaard, B. G., Wong, C. H. Y., Guettler, C.,
Petri, B., Burkhard, R., Wyss, M.,
LeMoual, H., Divinney, R.,
Thompson, G. C., Blackwood, J., Joffe, A. R., McCoy, K. D., Jenne, C. N., &
Kubes, P. (2018). Sex-hormone-driven innate antibodies protect females and
infants against EPEC infection. Nature
Immunology, 19(October), 1100-1111.
Shröder, J., Kahlke, V., Staubach, K., Zabel, P., &
Stüber, F. (1998). Gender Differences in Human
Sepsis. Arch. Surg., 133(11), 1200-1205.
Klein, S. L. & Flanagan, K. L. (2016). Sex Differences
in Immune Responses. Nature Reviews
Immunology,
16(October), 626-638.
John, Walter. [Walter John]. (2016, July 8). KUPFFER CELLS IN LIVER part 1 [Video
File] Retrieved
World of Microbiology and Immunology. (n.d.) Opsonization.
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N.I.H. U.S. National Library of Medicine. (2018, October 9).
C3 Gene. Retrieved from:
Intermountain Health Care. (n.d.) Enteropathogenic E. coli
Information for Patients. Retrieved
Ochoa, T. J. & Contreras. (2011). Enthropathogenic Escherichia coli infection in children. Current
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Goldsmith, S. J., Dickson, J. S., Barnhart, H. M., Toledo,
R. T., & Eiten-Miller, R. R. (1983). IgA,
IgG, IgM, and Lactoferrin Contents
of Human Milk During Early Lactation and the Effect of Processing and Storage. Journal of Food Protection 46(1), 4-7.
Morrow, A. L., Rangel, J. M. (2004). Human milk protection against
infectious diarrhea:
Implications for prevention and
clinical care. Seminars in Pediatric
Infectious Diseases 15(4), 221-228.
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