This study reports that prior infection of mice with parasitic worms can improve survival during subsequent septic peritonitis. In this model, a recent history of parasitosis with the hookworm-like nematode N. brasiliensis improves survival by enhancing clearance of K. pneumoniae bacteria infecting the peritoneum. The worms appear to accomplish this by provoking production of Th2 cytokines, such as IL-4, which primes mast cells to enhance their innate responses to bacteria. These suggest that intestinal worm infections may be mutually beneficial to the host by protecting them from subsequent bacterial infection.
The immune system is in a constant state of flux controlled in large part by the infectious organisms it encounters. These exposures educate the immune system such that it will clear repeat infections by the same microorganism and thereby limit potential harm to the host. More recent data has shown that an infection by one microorganism can provide heterologous protection from an unrelated organism 
. For example, latent herpesvirus infection improves survival from subsequent Listeria monocytogenes
infection by increasing Listeria
. Similarly, inhalation of Haemophilus influenzae
extracts improves survival from subsequent infections, including Streptococcus pneumoniae
, Klebsiella pneumoniae
, Aspergillus fumigatus
, and influenza A 
. Collectively, these studies show that prior exposure to infectious agents or extracts of them can favorably modulate the immune response to subsequent heterologous infections.
The present study reports parasitic infection with N. brasiliensis
favorably alter the immune response to a heterologous intraperitoneal infection with the bacterium K. pneumoniae
. The data show that mice previously infected with N. brasiliensis
have more neutrophil recruitment and higher intraperitoneal IL-6 levels early after K. pneumoniae
infection. These exaggerated immune responses are associated with improved bacterial clearance and host survival 
. Although an explanation for the enhanced neutrophil recruitment remains undefined, possibilities include activation of innate immune cells, such as mast cells, by products made by N. brasiliensis
or by mediators produced in response to the N. brasiliensis
infection. This study reports IL-4 as a candidate mediator produced in response to the N. brasiliensis
infection that can augment mast cell responses to subsequent K. pneumoniae
Prior work has established that mast cells play an essential role in regulating the immune response to severe bacterial infections and sepsis 
by secreting of TNF-α and tryptase, which promote recruitment of neutrophils to sites of infection  
, and IL-6, which potentiates neutrophil killing of bacteria 
. The finding that Nippo
mice have higher intraperitoneal IL-6 levels 4 h after infection and that IL-4-conditioned mast cells generate more IL-6 is consistent with the idea that mast cells are a source of the higher IL-6 levels in Nippo
mice. Determining whether mast cells are a source of IL-6 under these conditions, or other cells contribute will require further study. In prior work, we reported that increased intraperitoneal levels of IL-6 improve survival of septic DPPI −/−
. The finding that Nippo
mice have higher intraperitoneal IL-6 levels underscores the beneficial effects of locally produced IL-6 and suggests that increasing peritoneal IL-6 early in the course of infection benefits the host independent of its cellular source.
The observed mast cell dependence of the survival advantage of parasitized mice with bacterial peritonitis suggests that N. brasiliensis
infection changes mast cell behavior and that mast cell responses to bacterial infection are not static. This is consistent with reports that mast cell numbers and phenotypes change during parasitic infections 
. In addition, this study provides the first evidence that the phenotypic change produced by N. brasiliensis
infection in vivo or by conditioning with IL-4 in vitro protects mice from death from K. pneumoniae
-mediated septic peritonitis. These findings suggest that augmenting mast cell responses to bacteria could be therapeutic in severe bacterial infections and sepsis.
Although not required for worm expulsion, IL-4 is a major mediator of the host response to N. brasiliensis
. The improved survival of Nippo
mice appears to depend on IL-4 because the survival benefit is lost in mice lacking this cytokine (). Although IL-4-conditioned BMCMC are not phenocopies of peritoneal MC in Nippo
mice, the result that mast cell-deficient Wsh
mice reconstituted with IL-4-conditioned mast cells have better survival and elevated intraperitoneal IL-6 levels following K. pneumoniae
peritonitis suggests that conditioning of peritoneal mast cells by endogenously generated IL-4 in Nippo
mice could contribute to the survival benefit. The biochemical explanation for how IL-4 increases mast cell IL-6 production remains undefined. Because the heat-killed Klebsiella
was used as a stimulus, we suspect IL-4 is influencing there TLR signaling. Overall these findings are consistent with prior observations that over-expression of IL-4 improves survival in mice with sepsis and Pseudomonas
. Similarly, IL-4 stimulates production of the antimicrobial peptide LL37 in mast cells 
, showing that IL-4 can provoke a change in mast cells that could enhance bacterial clearance. Determining how IL-4 enhances mast cell responses in Nippo
mice and whether other Th2 cytokines similarly contribute to the protection requires further study.
Classically, parasite-host interactions are recognized to benefit the parasite and harm the host. This perspective has changed as it has become apparent that some parasites may provide a benefit to their host 
. For example, trypanosomes synthesize vitamin B6 and therefore can provide a source of the vitamin to infected rodents living in environments low in vitamin B6 
. The present study reports a novel way in which metazoan parasites may benefit their host: namely, by protecting them from a subsequent life-threatening bacterial infection. Because a live rodent is required for the life cycle of N. brasiliensis
, the survival benefit may mutually benefit the parasite by ensuring that the host survives and is available for the parasite to complete its life cycle. Thus, in the context of severe bacterial infection, N. brasiliensis
infection is mutually beneficial rather than parasitic. Whether similar mutually beneficial parasite-host interactions occur in infected humans remains to be examined.
In summary, the data presented here establish that prior infection with a hookworm-like intestinal parasite can improve survival from a severe Gram-negative bacterial infection. The survival benefit depends on mast cells and IL-4 and is associated with augmented neutrophil recruitment, secretion of IL-6 and accelerated bacterial clearance. The results suggest that host infection with metazoan parasites can be mutually beneficial and may reinforce co-evolution of parasite and host by protecting the host from death from bacterial infection.